Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors

ABSTRACT

Compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein: W is O, N—H, N—(C 1 -C 10  alkyl) or S; each X is independently CH or N; R 1  is a 5 to 7-membered saturated or unsaturated, optionally substituted heterocycle containing at least 1 heteroatom selected from N or O; R 2  is (LQ) m Y; and each R 3  is independently H, C 1 -C 10  alkyl, aryl or heteroaryl, are surprisingly found to be inhibitors of PI3K-p110δ, and therefore have utility in therapy.

This application is a continuation of U.S. Ser. No. 13/388,164 filedMar. 27, 2012, which is a National Stage Application of InternationalApplication Number PCT/GB2010/051370, filed Aug. 19, 2010, which claimspriority to Great Britain Application No. 0914594.7, filed Aug. 20, 2009and Great Britain Application No. 1005584.6, filed Apr. 1, 2010.

FIELD OF THE INVENTION

The present invention relates to novel compounds which act as inhibitorsof the class IA phosphoinositide 3-kinase enzyme, PI3K-p110δ, for thetreatment of cancer, immune and inflammatory diseases.

BACKGROUND OF THE INVENTION

The phosphoinositide 3-kinases (PI3Ks) constitute a family of lipidkinases involved in the regulation of a network of signal transductionpathways that control a range of cellular processes. PI3Ks areclassified into three distinct subfamilies, named class I, II, and IIIbased upon their substrate specificities. Class IA PI3Ks possess ap110α, p110β, or p110δ catalytic subunit complexed with one of threeregulatory subunits, p85α, p85β or p55δ. Class IA PI3Ks are activated byreceptor tyrosine kinases, antigen receptors, G-protein coupledreceptors (GPCRs), and cytokine receptors. The class IA PI3Ks primarilygenerate phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P₃), a secondmessenger that activates the downstream target AKT. The consequences ofbiological activation of AKT include tumour cell progression,proliferation, survival and growth, and there is significant evidencesuggesting that the PI3K/AKT pathway is dysregulated in many humancancers. Additionally, PI3K activity has been implicated inendocrinology, cardiovascular disease, immune disorders andinflammation. It has been established that PI3K-p110δ plays a criticalrole in the recruitment and activation of immune and inflammatory cells.PI3K-p110δ is also upregulated in a number of human tumours and plays akey role in tumour cell proliferation and survival.

Compounds which are able to modulate p110δ activity have importanttherapeutic potential in cancer and immune and inflammatory disorders.

WO2006/046035 describes fused pyrimidines, which have activity asinhibitors of PI3K. The compounds disclosed therein exhibit selectivityfor class Ia PI3Ks, notably p110δ.

SUMMARY OF THE INVENTION

The present invention is a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is O, N—H, N—(C₁-C₁₀ alkyl) or S;

each X is independently CH or N;

R¹ is a 5 to 7-membered saturated or unsaturated, optionally substitutedheterocycle containing at least 1 heteroatom selected from N or O;

R² is (LQ)_(m)Y;

each L is independently a direct bond. C₁-C₁₀ alkylene, C₂-C₁₀alkenylene, C₂-C₁₀ alkynylene, arylene or C₃-C₁₀ cycloalkylene;

each Q is independently a direct bond, heteroarylene, a heterocyclelinker, —O—, —NR³—, —C(O)—, —C(O)NR₃—, —SO₂—, —SO₂—NR³—, —N—C(O)—NR³—,—N—SO₂—NR³, halogen, —C(halogen)_(a)(R³ _((2-a)))—, —NR⁴R⁵—, —C(O)NR⁴R⁵,where R⁴ and R⁵ together with the nitrogen to which they are attachedform a 5 to 7-membered heterocycle linker;

m is from 0 to 5;

Y is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,aryl, C₃-C₁₀ cycloalkyl, heterocycle, heteroaryl, —OR³, —N(R³)₂,—C(O)R³, —C(O)OR₃, —C(O)N(R³)₂, —N(R³)₂, —SO₂—R³, —SO₂—N(R³)₂,—N—C(O)—N(R³)₂, —N—SO₂—N(R³)₂, halogen, —C(halogen)_(b)R³ _((3-b)), —CN,—NR⁴R⁵—, —C(O)NR⁴R⁵, where R⁴ and R⁵ together with the nitrogen to whichthey are attached form a 5- to 7-membered heterocycle;

b is from 1 to 3;

a is 1 or 2; and

each R³ is independently H. C₁-C₁₀ alkyl, aryl or heteroaryl.

It has been surprisingly found that these compounds are inhibitors ofPI3K-p110δ. Some of the compounds disclosed herein may additionallyinhibit PI3K-p110β.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein, alkyl means a C₁-C₁₀ alkyl group, which can be linear orbranched. Preferably, it is a C₁-C₆ alkyl moiety. More preferably, it isa C₁-C₄ alkyl moiety. Examples include methyl, ethyl, n-propyl andt-butyl. It may be divalent, e.g. propylene.

As used herein, cycloalkyl contains from 3 to 10 carbon atoms. It may bemonovalent or divalent.

As used herein, alkenyl means a C₂-C₁₀ alkenyl group. Preferably, it isa C₂-C₆ alkenyl group. More preferably, it is a C₂-C₄ alkenyl group. Thealkenyl radicals may be mono- or di-saturated, more preferablymonosaturated. Examples include vinyl, allyl, 1-propenyl, isopropenyland 1-butenyl. It may be divalent, e.g. propenylene

As used herein, alkynyl is a C₂-C₁₀ alkynyl group which can be linear orbranched. Preferably, it is a C₂-C₄ alkynyl group or moiety. It may bedivalent.

Each of the C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl and C₂-C₁₀ alkynyl groups maybe optionally substituted with each other, i.e. C₁-C₁₀ alkyl optionallysubstituted with C₂-C₁₀ alkenyl. They may also be optionally substitutedwith aryl, cycloalkyl (preferably C₃-C₁₀), aryl or heteroaryl.

As used herein, aryl means a monocyclic, bicyclic, or tricyclicmonovalent or divalent aromatic radical, such as phenyl, biphenyl,naphthyl, anthracenyl, which can be optionally substituted with up tofive substituents preferably selected from the group of C₁-C₆ alkyl,hydroxy, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, amino,C₁-C₃ mono alkylamino, C₁-C₃ bis alkylamino, C₁-C₃ acylamino, C₁-C₃aminoalkyl, mono (C₁-C₃ alkyl) amino C₁-C₃ alkyl, bis(C₁-C₃ alkyl) aminoC₁-C₃ alkyl, C₁-C₃-acylamino, C₁-C₃ alkyl sulfonylamino, halo, nitro,cyano, trifluoromethyl, carboxy, C₁-C₃ alkoxycarbonyl, aminocarbonyl,mono C₁-C₃ alkyl aminocarbonyl, bis C₁-C₃ alkyl aminocarbonyl, —SO₃H,C₁-C₃ alkylsulfonyl, aminosulfonyl, mono C₁-C₃ alkyl aminosulfonyl andbis C₁-C₃-alkyl aminosulfonyl.

As used herein, heteroaryl means a monocyclic, bicyclic or tricyclicmonovalent aromatic radical containing up to four heteroatoms selectedfrom oxygen, nitrogen and sulfur, such as thiazolyl, tetrazolyl,imidazolyl, oxazolyl, isoxazolyl, thienyl, pyrazolyl, pyridinyl,pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, said radicalbeing optionally substituted with up to three substituents preferablyselected from the group of C₁-C₆ alkyl, hydroxy, C₁-C₃ hydroxyalkyl,C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, amino, C₁-C₃ mono alkylamino, C₁-C₃ bisalkylamino, C₁-C₃ acylamino, C₁-C₃ aminoalkyl, mono (C₁-C₃ alkyl) aminoC₁-C₃ alkyl, bis (C₁-C₃ alkyl) amino C₁-C₃ alkyl, C₁-C₃-acylamino, C₁-C₃alkyl sulfonylamino, halo, nitro, cyano, trifluoromethyl, carboxy, C₁-C₃alkoxycarbonyl, aminocarbonyl, mono C₁-C₃ alkyl aminocarbonyl, bis C₁-C₃alkyl aminocarbonyl, —SO₃H, C₁-C₃ alkylsulphonyl, aminosulfonyl, monoC₁-C₃ alkyl aminosulfonyl and bis C₁-C₃-alkyl aminosulfonyl.

As used herein, heterocycle is a mono- or di-valent carbocyclic radicalcontaining up to 4 heteroatoms selected from oxygen, nitrogen andsulphur. The word ‘linker’ has been used herein to mean di-valent. Ifthe heterocycle is a di-valent linker, the heterocycle may be attachedto neighbouring groups through a carbon atom, or through on of theheteroatoms, e.g. a N.

The heterocyclic ring may be mono- or di-saturated. The radical may beoptionally substituted with up to three substituents independentlyselected from C₁-C₆ alkyl, hydroxy, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy,C₁-C₃ haloalkoxy, amino, C₁-C₃ mono alkylamino, C₁-C₃ bis alkylamino,C₁-C₃ acylamino, C₁-C₃ aminoalkyl, mono (C₁-C₃ alkyl) amino C₁-C₃ alkyl,bis (C₁-C₃ alkyl) amino C₁-C₃ alkyl, C₁-C₃-acylamino, C₁-C₃ alkylsulfonylamino, halo e.g. F, nitro, cyano, trifluoromethyl, carboxy,C₁-C₃ alkoxycarbonyl, aminocarbonyl, mono C₁-C₃ alkyl aminocarbonyl, bisC₁-C₃ alkyl aminocarbonyl, —SO₃H, C₁-C₃ alkylsulphonyl, aminosulfonyl,mono C₁-C₃ alkyl aminosulfonyl and bis C₁-C₃-alkyl aminosulfonyl.

As used herein, the above groups can be followed by the suffix-ene. Thismeans that the group is divalent, i.e. a linker group.

In a preferred embodiment R¹ is represented by any of the followingstructures:

Preferably, W is S. More preferably, W is O.

R² may be attached to any suitable atom on the aryl group, as depictedin general formula I. Preferably, it is attached to atoms 2 or 3, asshown below:

It may also be attached to atoms 1 or 4.

Preferably, a compound of the invention is of the structure:

As above, the placing of any of the R² and R³ groups has nosignificance, other than the group must be attached to that particulararyl system. In other words, the R2 group has 4 possible bondingpositions, the first R³ group has only 2 possible positions ofattachment, and the other R³ group may be attached to one of 3positions.

More preferably, a compound of the invention has the formula:

Preferably the 6,5-ring system in formula I is an indole. Alternatively,it may be a benzo-fused pyrrolo, a pyridyl-fused pyrrolo, apyridazinyl-fused pyrrolo, a pyrazinyl-fused pyrrolo, or apyrimidinyl-fused pyrrolo.

Preferably, both of the R³ groups that are attached to the 6,5 ringsystem in formula I are H.

Preferably, at least one Q is —C(O)—NR⁴R⁵, where R⁴ and R⁵ together withthe nitrogen to which they are attached form a 5 to 7-memberedheterocycle linker. More preferably, Q is

Preferably, at least one Q is —NR³—

Preferably, at least one Q is a direct bond.

Preferably, at least one L is C₁-C₁₀ alkylene or at least one L isC₂-C₁₀ alkenylene, or at least one L is cycloalkylene.

Preferably Y is N(R³)₂. More preferably, Y is a heteroaryl, such as anindolyl, or Y is a heterocycle.

Preferably R² is H. Preferably R² is —(C₁-C₁₀ alkylene)-N(R³)₂. Morepreferably, R² is —CH₂—N(CH₃)₂. R² may also be —(C₂-C₁₀alkenylene)-C(O)—N(R⁴R⁵)—R³, where R₄ and R₅ together with the nitrogento which they are attached form a 5- to 7-membered heterocycle. Morepreferably, R² is

Still more preferably, R comprises —(C₁-C₁₀ alkylene)-NR⁴R⁵ or R²comprises —(C₁-C₁₀ alkylene)-NR³—(C₁-C₁₀ alkylene)-cycloakyl, whereinR², R⁴ and R⁵ are as defined above.

Preferably m is 0, 1 or 2.

Examples of structures embodying the invention are:

A pharmaceutical composition of the invention typically contains up to85 wt % of a compound of the invention. More typically, it contains upto 50 wt % of a compound of the invention. Preferred pharmaceuticalcompositions are sterile and pyrogen-free. Further, the pharmaceuticalcompositions provided by the invention typically contain a compound ofthe invention which is a substantially pure optical isomer. Preferably,the pharmaceutical composition comprises a pharmaceutically acceptablesalt form of a compound of the invention.

As used herein, a pharmaceutically acceptable salt is a salt with apharmaceutically acceptable acid or base. Pharmaceutically acceptableacids include both inorganic acids such as hydrochloric, sulphuric,phosphoric, diphosphoric, hydrobromic or nitric acid and organic acidssuch as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric,benzoic, acetic, methanesulphonic, ethanesulphonic, salicylic, stearic,benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptablebases include alkali metal (e.g. sodium or potassium) and alkali earthmetal (e.g. calcium or magnesium) hydroxides and organic bases such asalkyl amines, aryl amines or heterocyclic amines.

For the avoidance of doubt, the present invention also embraces prodrugswhich react in vivo to give a compound of the present invention.

The compounds of the invention may be prepared by synthetic routes thatwill be apparent to those skilled in the art, e.g. based on theExamples.

The compounds of the invention and compositions comprising them may beadministered in a variety of dosage forms. In one embodiment, apharmaceutical composition comprising a compound of the invention may beformulated in a format suitable for oral, rectal, parenteral, intranasalor transdermal administration or administration by inhalation or bysuppository. Typical routes of administration are parenteral, intranasalor transdermal administration or administration by inhalation.

The compounds of the invention can be administered orally, for exampleas tablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules. Preferred pharmaceutical compositions of theinvention are compositions suitable for oral administration, for exampletablets and capsules.

The compounds of the invention may also be administered parenterally,whether subcutaneously, intravenously, intramuscularly, intrasternally,transdermally or by infusion techniques. The compounds may also beadministered as suppositories.

The compounds of the invention may also be administered by inhalation.An advantage of inhaled medications is their direct delivery to the areaof rich blood supply in comparison to many medications taken by oralroute. Thus, the absorption is very rapid as the alveoli have anenormous surface area and rich blood supply and first pass metabolism isbypassed. A further advantage may be to treat diseases of the pulmonarysystem, such that delivering drugs by inhalation delivers them to theproximity of the cells which are required to be treated.

The present invention also provides an inhalation device containing sucha pharmaceutical composition. Typically said device is a metered doseinhaler (MDI), which contains a pharmaceutically acceptable chemicalpropellant to push the medication out of the inhaler.

The compounds of the invention may also be administered by intranasaladministration. The nasal cavity's highly permeable tissue is veryreceptive to medication and absorbs it quickly and efficiently, more sothan drugs in tablet form. Nasal drug delivery is less painful andinvasive than injections, generating less anxiety among patients. Bythis method absorption is very rapid and first pass metabolism isusually bypassed, thus reducing inter-patient variability. Further, thepresent invention also provides an intranasal device containing such apharmaceutical composition.

The compounds of the invention may also be administered by transdermaladministration. The present invention therefore also provides atransdermal patch containing a compound of the invention.

The compounds of the invention may also be administered by sublingualadministration. The present invention therefore also provides asub-lingual tablet comprising a compound of the invention.

A compound of the invention may also be formulated with an agent whichreduces degradation of the substance by processes other than the normalmetabolism of the patient, such as anti-bacterial agents, or inhibitorsof protease enzymes which might be the present in the patient or incommensural or parasite organisms living on or within the patient, andwhich are capable of degrading the compound.

Liquid dispersions for oral administration may be syrups, emulsions andsuspensions.

Suspensions and emulsions may contain as carrier, for example a naturalgum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol. The suspension orsolutions for intramuscular injections may contain, together with theactive compound, a pharmaceutically acceptable carrier, e.g. sterilewater, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and ifdesired, a suitable amount of lidocaine hydrochloride.

Solutions for injection or infusion may contain as carrier, for example,sterile water or preferably they may be in the form of sterile, aqueous,isotonic saline solutions.

The compounds of the present invention can be used in both the treatmentand prevention of cancer and can be used in a monotherapy or in acombination therapy. When used in a combination therapy, the compoundsof the present invention are typically used together with small chemicalcompounds such as platinum complexes, anti-metabolites, DNAtopoisomerase inhibitors, radiation, antibody-based therapies (forexample herceptin and rituximab), anti-cancer vaccination, gene therapy,cellular therapies, hormone therapies or cytokine therapy.

In one embodiment of the invention a compound of the invention is usedin combination with another chemotherapeutic or antineoplastic agent inthe treatment of a cancer. Examples of such other chemotherapeutic orantineoplastic agents include platinum complexes including cisplatin andcarboplatin, mitoxantrone, vinca alkaloids for example vincristine andvinblastine, anthracycline antibiotics for example daunorubicin anddoxorubicin, alkylating agents for example chlorambucil and melphalan,taxanes for example paclitaxel, antifolates for example methotrexate andtomudex, epipodophyllotoxins for example etoposide, camptothecins forexample irinotecan and its active metabolite SN38 and DNA methylationinhibitors for example the DNA methylation inhibitors disclosed inWO02/085400.

According to the invention, therefore, products are provided whichcontain a compound of the invention and another chemotherapeutic orantineoplastic agent as a combined preparation for simultaneous,separate or sequential use in alleviating a cancer. Also providedaccording to the invention is the use of compound of the invention inthe manufacture of a medicament for use in the alleviation of cancer bycoadministration with another chemotherapeutic or antineoplastic agent.The compound of the invention and the said other agent may beadministrated in any order. In both these cases the compound of theinvention and the other agent may be administered together or, ifseparately, in any order as determined by a physician.

The PI3K inhibitors of the present invention may also be used to treatabnormal cell proliferation due to insults to body tissue duringsurgery. These insults may arise as a result of a variety of surgicalprocedures such as joint surgery, bowel surgery, and cheloid scarring.Diseases that produce fibrotic tissue that may be treated using the PI3Kinhibitors of the present invention include emphysema. Repetitive motiondisorders that may be treated using the present invention include carpaltunnel syndrome. An example of a cell proliferative disorder that may betreated using the invention is a bone tumour.

Proliferative responses associated with organ transplantation that maybe treated using PI3K inhibitors of the invention include proliferativeresponses contributing to potential organ rejections or associatedcomplications. Specifically, these proliferative responses may occurduring transplantation of the heart, lung, liver, kidney, and other bodyorgans or organ systems.

Abnormal angiogenesis that may be treated using this invention includethose abnormal angiogenesis accompanying rheumatoid arthritis,ischemic-reperfusion related brain edema and injury, cortical ischemia,ovarian hyperplasia and hypervascularity, polycystic ovary syndrome,endometriosis, psoriasis, diabetic retinopathy, and other ocularangiogenic diseases such as retinopathy of prematurity (retrolentalfibroplastic), macular degeneration, corneal graft rejection,neuroscular glaucoma and Oster Webber syndrome.

Examples of diseases associated with uncontrolled angiogenesis that maybe treated according to the present invention include, but are notlimited to retinal/choroidal neovascularisation and cornealneovascularisation. Examples of diseases which include some component ofretinal/choroidal neovascularisation include, but are not limited to,Best's diseases, myopia, optic pits, Stargart's diseases, Paget'sdisease, vein occlusion, artery occlusion, sickle cell anaemia, sarcoid,syphilis, pseudoxanthoma elasticum carotid apo structive diseases,chronic uveitis/vitritis, mycobacterial infections, Lyme's disease,systemic lupus erythematosus, retinopathy of prematurity, Eale'sdisease, diabetic retinopathy, macular degeneration, Bechet's diseases,infections causing a retinitis or chroiditis, presumed ocularhistoplasmosis, pars planitis, chronic retinal detachment,hyperviscosity syndromes, toxoplasmosis, trauma and post-lasercomplications, diseases associated with rubesis (neovascularisation ofthe angle) and diseases caused by the abnormal proliferation offibrovascular or fibrous tissue including all forms of proliferativevitreoretinopathy. Examples of corneal neovascularisation include, butare not limited to, epidemic keratoconjunctivitis, Vitamin A deficiency,contact lens overwear, atopic keratitis, superior limbic keratitis,pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis,diabetic retinopathy, retinopathy of prematurity, corneal graftrejection, Mooren ulcer, Terrien's marginal degeneration, marginalkeratolysis, polyarteritis, Wegener sarcoidosis, Scleritis, periphigoidradial keratotomy, neovascular glaucoma and retrolental fibroplasia,syphilis, Mycobacteria infections, lipid degeneration, chemical burns,bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpeszoster infections, protozoan infections and Kaposi sarcoma.

Chronic inflammatory diseases associated with uncontrolled angiogenesismay also be treated using PI3K inhibitors of the present invention.Chronic inflammation depends on continuous formation of capillarysprouts to maintain an influx of inflammatory cells. The influx andpresence of the inflammatory cells produce granulomas and thus maintainsthe chronic inflammatory state. Inhibition of angiogenesis using a PI3Kinhibitor alone or in conjunction with other anti-inflammatory agentsmay prevent the formation of the granulomas and thus alleviate thedisease. Examples of chronic inflammatory diseases include, but are notlimited to, inflammatory bowel diseases such as Crohn's disease andulcerative colitis, psoriasis, sarcoidosis, and rheumatoid arthritis.

Inflammatory bowel diseases such as Crohn's disease and ulcerativecolitis are characterised by chronic inflammation and angiogenesis atvarious sites in the gastrointestinal tract. For example, Crohn'sdisease occurs as a chronic transmural inflammatory disease that mostcommonly affects the distal ileum and colon but may also occur in anypart of the gastrointestinal tract from the mouth to the anus andperianal area. Patients with Crohn's disease generally have chronicdiarrhea associated with abdominal pain, fever, anorexia, weight lossand abdominal swelling. Ulcerative colitis is also a chronic,nonspecific, inflammatory and ulcerative disease arising in the colonicmucosa and is characterised by the presence of bloody diarrhea. Theseinflammatory bowel diseases are generally caused by chronicgranulomatous inflammation throughout the gastrointestinal tract,involving new capillary sprouts surrounded by a cylinder of inflammatorycells. Inhibition of angiogenesis by these inhibitors should inhibit theformation of the sprouts and prevent the formation of granulomas.Inflammatory bowel diseases also exhibit extra intestinalmanifestations, such as skin lesions. Such lesions are characterized byinflammation and angiogenesis and can occur at many sites other thegastrointestinal tract. Inhibition of angiogenesis by PI3K inhibitorsaccording to the present invention can reduce the influx of inflammatorycells and prevent lesion formation.

Sarcoidosis, another chronic inflammatory disease, is characterized as amultisystem granulomatous disorder. The granulomas of this disease canform anywhere in the body. Thus, the symptoms depend on the site of thegranulomas and whether the disease is active. The granulomas are createdby the angiogenic capillary sprouts providing a constant supply ofinflammatory cells. By using PI3K inhibitors according to the presentinvention to inhibit angiogenesis, such granulomas formation can beinhibited. Psoriasis, also a chronic and recurrent inflammatory disease,is characterised by papules and plaques of various sizes. Treatmentusing these inhibitors alone or in conjunction with otheranti-inflammatory agents should prevent the formation of new bloodvessels necessary to maintain the characteristic lesions and provide thepatient relief from the symptoms.

Rheumatoid arthritis (RA) is also a chronic inflammatory diseasecharacterised by non-specific inflammation of the peripheral joints. Itis believed that the blood vessels in the synovial lining of the jointsundergo angiogenesis. In addition to forming new vascular networks, theendothelial cells release factors and reactive oxygen species that leadto pannus growth and cartilage destruction. The factors involved inangiogenesis may actively contribute to, and help maintain, thechronically inflamed state of rheumatoid arthritis. Treatment using PI3Kinhibitors according to the present invention alone or in conjunctionwith other anti-RA agents may prevent the formation of new blood vesselsnecessary to maintain the chronic inflammation.

Preferably, the condition is cancer, notably leukaemias includingchronic myelogenous leukaemia and acute myeloid leukaemia, lymphomas,solid tumours, and PTEN-negative tumours including PTEN-negativehaematological, breast, lung, endometrial, skin, brain and prostratecancers (where PTEN refers to “phosphatise and tensin homolog deleted onchromosome 10”). More preferably, the condition to be treated by acompound of the invention is rheumatoid arthritis, asthma, chronicobstructive pulmonary disease (COPD), multiple sclerosis, psoriasis andother inflammatory skin disorders, systemic lupus erythematosus,inflammatory bowel disease, and organ transplant rejection. Morepreferably,

The invention will now be illustrated by the following Examples.

EXAMPLES Example A2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine

i. 3-Amino-thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester, 2

Under Ar(g), 2-chloro-3-pyridinecarbonitrile, 1, (3.026 g, 21.8 mmol)and sodium carbonate (2.511 g, 23.7 mmol) were dissolved in dry ethanol(11.5 mL). Ethyl-2-meracaptacetate (3.1 mL, 28.3 mmol) was then added,and the reaction mixture was heated at reflux for 4 h 35 min. Thereaction was then cooled to rt; water (140 mL) was then added, at whichpoint a precipitate formed, and the resulting reaction mixture wassubsequently stirred for a further 30 min. The precipitate was filtered,washed with water (2×15 mL) and the resulting residue collected anddried under vacuum to furnish 2 (4.435 g, 20 mmol, 92%) as an orangesolid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.70 (dd, J=4.6, 1.44 Hz, 1H), 7.96 (dd,J=8.1, 1.57 Hz, 1H), 7.33 (dd, J=8.2, 4.6 Hz, 1H), 5.92 (br. s, 2H),4.38 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

MS (ES⁺) 223.0 (100%, [M+H]⁺).

ii. 1H-Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-2,4-dione, 3

Under Ar(g), compound 2 (518 mg, 2.33 mmol) and urea (1.143 g, 19.0mmol) were combined and heated to 190° C. with stirring for 2.5 h. Thereaction mixture was then cooled, and 1M NaOH (10 mL) was added whilethe mixture was warm; the resulting mixture was then stirred andfiltered. The filtrate was acidified with 1M HCl, and a precipitateformed; the mixture was then filtered and the solid collected driedunder vacuum to furnish 3 as an orange/brown solid (125 mg, 0.574 mmol,25%).

¹H NMR (400 MHz, DMSO-d₆) δ_(H): 12.40 (s, 1H), 11.60 (s, 1H), 8.80-8.73(m, 2H), 7.63 (dd, J=8.2, 4.6 Hz, 1H).

MS (ES⁻) 217.9 (100%, [M−H]⁻).

iii. 2,4-Dichloro-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine, 4

To compound 3 (15.2 mg, 0.070 mmol) and PCl₅ (592.2 mg, 2.84 mmol) underAr(g) was added POCl₃ (2 mL), and the resulting reaction mixture wasthen heated at reflux for 26 h. The POCl₃ was then removed in vacuo toyield a solid residue which was slowly added to crushed ice (4 g) withstirring. The aqueous phase was then extracted with CHCl₃, the layerswere separated and the organic phase was washed with water to remove allthe remaining phosphoric acid. The organic layer was subsequently dried(MgSO₄) and concentrated in vacuo to give 4 (3.8 mg, 0.015 mmol, 21%).

¹H NMR (300 MHz, CDCl₃) δ_(H): 8.93 (dd, J=4.7, 1.7 Hz, 1H), 8.78 (dd,J=7.9, 1.5 Hz, 1H), 7.61 (m, 1H).

MS (ES⁺) 255.9 (100%, [M+H]⁺).

iv. 2-Chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine,5

To 4 (34.3 mg, 0.14 mmol) in methanol (1.5 mL) was added morpholine (25μL, 0.29 mmol) dropwise, and the resulting reaction was stirred for 1 hat rt. The mixture was then filtered, washed with water and thenmethanol, and the remaining solid was dissolved in CH₂Cl₂ andconcentrated in vacuo to furnish 5 as a pale brown solid (30.1 mg, 0.098mmol, 73%).

¹H NMR (300 MHz, CDCl₃) δ_(H): 8.83 (br. s, 1H), 8.72 (dd, J=8.0, 1.51Hz, 1H), 7.53 (m, 1H), 4.11-4.05 (m, 4H), 3.94-3.88 (m, 4H).

MS (ES⁺) 307.0 (100%, [M+H]⁺).

v.2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine,A

Under Ar(g), to a mixture of compound 5 (14.97 mg, 0.049 mmol),indole-4-boronic acid (8.70 mg, 0.054 mmol),dichloro-bis(triphenylphosphine)palladium (II) (1.81 mg, 0.0026 mmol)and sodium hydrogen carbonate (12.50 mg, 0.15 mmol) was added ethanol(0.75 mL) followed by toluene (1.25 mL) and then water (0.35 mL). Thereaction was then heated in a microwave at 120° C. (300 W) for 1 h. Thereaction mixture was then cooled to rt, and was partitioned betweenCH₂Cl₂ and water, and the organic layer was then separated, dried(MgSO₄) and concentrated in vacuo. Purification by flash columnchromatography on silica (eluant 0:1-1:99) MeOH/CH₂Cl₂) furnished A (1mg, 0.0026 mol, 5%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ_(H): 8.91 (d, J=8.3 Hz, 1H) 8.82 (dd, J=4.7,1.7 Hz, 1H) 8.40-8.33 (m, 2H), 7.72 (br. s, 1H), 7.54 (d, J=1.1 Hz, 1H),7.54 (dd, J=12.8, 4.9 Hz, 1H), 7.42-7.32 (m, 2H), 4.19-4.11 (m, 4H),4.01-3.93 (m, 4H).

MS (ES⁺) 388.1 (100%, [M+H]⁺).

Example B2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine

i. 3-Amino-furo[2,3-b]pyridine-2-carboxylic acid ethyl ester, 2

2-Chloro-3-pyridinecarbonitrile, 1, (4.00 g, 28.9 mmol), Cs₂CO₃ (282 g,86.6 mmol) and ethyl glycolate (3 mL, 31.7 mmol) were placed in a flaskunder Ar(g). Dry NMP was added, and the suspension was heated at 75° C.for 20 h with vigorous stirring. The reaction mixture was cooled to rt,whereupon water (200 mL) and Et₂O (3×100 mL) were added. The organiclayers were combined, washed with water (3×15 mL) before being dried(MgSO₄) and concentrated in vacuo. Purification by flash columnchromatography on silica (eluant 15-40% EtOAc/Hex) gave 2 (2.41 g, 11.7mmol, 40%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.51 (dd, J=5.0, 2.0 Hz, 1H), 7.96 (dd,J=8.0, 2.0 Hz, 1H), 7.23-7.28 (m, 1H), 4.44 (q, J=7.0 Hz, 2H), 4.01 (br.s., 2H), 1.44 (t, J=7.0 Hz, 3H).

MS (ES⁺) 229 (100%, [M+Na]⁺).

ii. 1H-Pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine-2,4-dione, 3

Under Ar(g), and at 0° C., to a solution of compound 2 (1.189 g, 5.77mmol) in CH₂Cl₂ (20 mL) was added dropwise chlorosulfonyl isocyanate(0.55 mL, 6.34 mmol). The reaction mixture was allowed to warm to rt andafter 4 h it was concentrated in vacuo. Water (20 mL) was added, and thesuspension was stirred vigorously while heating to 70° C. for 10 min [MSanalysis showed formation of the urea intermediate was complete]. Themixture was then cooled and filtered, washing with water. The resultingsolid cake (0.87 g) was subsequently suspended in water (61 mL) and NaOH(3.15 g) was added. After 1 h stirring, LCMS analysis confirmed that thereaction had gone to completion. The mixture was then filtered, washingwith water, to furnish 3 (460 mg, 2.3 mmol, 40%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ_(H): 12.06 (br. s., 1H), 11.49 (br. s., 1H),8.60 (dd, J=5.0, 1.5 Hz, 1H), 8.43 (dd, J=8.0, 2.0 Hz, 1H), 7.56 (dd,J=8.0, 5.0 Hz, 1H).

MS (ES⁻) 202 (100%, [M−H]⁻).

iii. 2,4-Dichloro-pyrido[3′2′:4,5]furo[3,2-d]pyrimidine, 4

To compound 3 (0.14 g, 0.70 mmol) and PCl₅ (2.4 g, 2.84 mmol) underAr(g) was added POCl₃ (8 mL), and the resulting reaction mixture wasthen heated at reflux for 20 h. After the mixture had been cooled to rtit was poured onto crushed ice (200 mL) with vigorous stirring. Theaqueous phase was then extracted with CH₂Cl₂ (3×50 mL). The combinedorganic layers were subsequently dried (MgSO₄) and concentrated in vacuoto give 4 (66 mg, 0.28 mmol, 40%) as an off-white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.80 (dd, J=5.0, 1.5 Hz, 1H), 8.64 (dd,J=8.0, 2.0 Hz, 1H), 7.61 (dd, J=7.5, 5.0 Hz, 1H).

MS (ES⁺) 240 (100%, [M+H]⁺).

iv. 2-Chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine 5

To a solution of 4 (64 mg, 0.27 mmol) in dry methanol (10 mL) was addedmorpholine (55 μL, 0.62 mmol) dropwise, and the resulting reaction wasstirred for 2 h at rt. The resulting precipitate was then filtered,washed with water and then a mixture of 5:1 methanol/water, and theremaining solid was dried in vacuo to furnish 5 (50 mg, 0.17 mmol, 64%)as a white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.63 (dd, J=5.0, 2.0 Hz, 1H), 8.52 (dd,J=7.5, 2.0 Hz, 1H), 7.48 (dd, J=7.5, 5.0 Hz, 1H), 4.10-4.23 (m, 4H),3.86-3.91 (m, 4H).

MS (ES⁻) 291 (100%, [M+H]⁺).

v.2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,B

Under Ar(g), to a mixture of compound 5 (25 mg, 0.086 mmol),indole-4-boronic acid (15.2 mg, 0.095 mmol),dichloro-bis(triphenylphosphine)palladium (II) (3 mg, 0.004 mmol) andsodium hydrogen carbonate (22 mg, 0.26 mmol) was added ethanol (1 mL)followed by toluene (1.6 mL) and then water (0.5 mL). The reactionmixture was then heated in a microwave at 120° C. (300 W) for 45 min,and was subsequently cooled to rt; the mixture was then partitionedbetween CH₂Cl₂ and water, and the organic layer was separated, dried(MgSO₄) and concentrated in vacuo. Purification by flash columnchromatography on silica (eluant 30-60% EtOAc/Hex) furnished B (24.5 mg,0.067 mol, 77%) as an off-white solid.

¹H NMR (400 MHz, 19:1 CDCl₃/CD₃OD) δ_(H): 8.94 (br. s., 1H), 8.51 (dd,J=7.5, 2.0 Hz, 1H), 8.40 (dd, J=5.0, 2.0 Hz, 1H), 7.96 (d, J=7.5 Hz,1H), 7.26-7.35 (m, 3H), 7.08-7.18 (m, 2H), 4.02-4.11 (m, 4H), 3.71-3.79(m, 4H). ¹³C NMR (100 MHz, 19:1 CDCl₃/CD₃OD) δ_(C): 162.6, 161.7, 149.4,148.9, 147.0, 137.0, 133.0, 132.3, 130.3, 126.6, 125.2, 121.6, 121.5,120.4, 115.5, 113.2, 103.7, 67.0, 45.9.

MS (ES⁺) 372 (100%, [M+H]⁺).

Example C4-Morpholin-4-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3′,2′:4,5]thieno[3,2d]pyrimidine

i. 3-Amino-thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester, 2

2-Chloro-3-pyridinecarbonitrile, 1, (3.026 g, 21.8 mmol) and sodiumcarbonate (2.511 g, 237 mmol) were dissolved in dry ethanol (11.5 mL)under Ar(g). Ethyl-2-meracaptacetate (3.1 mL, 28.3 mmol) was then added,and the reaction mixture was heated at reflux for 4.5 h. The reactionmixture was then cooled to rt; water (140 mL) was added, at which pointa precipitate formed, and the resulting reaction mixture wassubsequently stirred for a further 30 min. The precipitate was filtered,washed with water (2×15 mL) and the resulting residue collected anddried under vacuum to furnish 2 (4.435 g, 20 mmol, 92%) as an orangesolid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.70 (dd, J=4.6, 1.44 Hz, 1H), 7.96 (dd,J=8.1, 1.57 Hz, 1H), 7.33 (dd, J=8.2, 4.6 Hz, 1H), 5.92 (br. s, 2H),4.38 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

MS (ES⁺) 223.0 (100%, [M+H]⁺).

ii. 1H-Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-2,4-dione, 3

Compound 2 (518 mg, 2.33 mmol) and urea (1.143 g, 19.0 mmol) werecombined and heated to 190° C. with stirring for 2.5 h. The reactionmixture was then cooled, and 1M NaOH (10 mL) was added while the mixturewas warm; the resulting mixture was then stirred and filtered. Theaqueous layer was acidified with 1M HCl, and a precipitate formed; themixture was then filtered and the solid collected dried under vacuum tofurnish 3 as an orange/brown solid (125 mg, 0.574 mmol, 25%).

¹H NMR (400 MHz, DMSO-d) δ_(H): 12.40 (s, 1H), 11.60 (s, 1H), 8.80-8.73(m, 2H), 7.63 (dd, J=8.2, 4.6 Hz, 1H).

MS (ES⁻) 217.9 (100%, [M−H]⁻).

iii. 2,4-Dichloro-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine, 4

To compound 3 (15.2 mg, 0.070 mmol) and PCl₅ (592 mg, 2.84 mmol) underAr(g) was added POCl₃ (2 mL), and the resulting reaction mixture wasthen heated at reflux for 26 h. The POCl₃ was then removed in vacuo tofurnish a solid residue, which was slowly added to crushed ice (50 g)with stirring. The aqueous phase was then extracted with CH₂Cl₂, thelayers were separated and the organic phase was washed with water toremove all the remaining phosphoric acid. The organic layer wassubsequently dried (MgSO₄) and concentrated in vacuo to give 4 (3.8 mg,0.015 mmol, 21%).

¹H NMR (300 MHz, CDCl₃) δ_(H): 8.93 (dd, J=4.7, 1.7 Hz, 1H), 8.78 (dd,J=7.9, 1.5 Hz, 1H), 7.61 (m, 1H).

MS (ES⁺) 255.9 (100%, [M+H]⁺).

iv. 2-Chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine,5

To compound 4 (34.3 mg, 0.14 mmol) in dry methanol (1.5 mL) was addedmorpholine (25 μL, 0.29 mmol) in a dropwise fashion, and the resultingmixture was stirred for 1 h at rt. The mixture was then filtered, washedwith water and then methanol, and the remaining solid was dissolved inCH₂Cl₂ and concentrated in vacuo to furnish 5 as a pale brown solid(30.1 mg, 0.098 mmol, 73%).

¹H NMR (300 MHz, CDCl₃) δ_(H): 8.83 (br. s, 1H), 8.72 (dd, J=8.0, 1.51Hz, 1H), 7.53 (m, 1H), 4.11-4.05 (m, 4H), 3.94-3.88 (m, 4H).

MS (ES⁺) 307.0 (100%, [M+H]⁺).

v.4-Morpholin-4-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3′,2′:4,5]thieno[3,2d]pyrimidine,C

To a mixture of compound 5 (16.0 mg, 0.052 mmol), 7-azaindole-4-boronicacid pinacol ester (14.3 mg, 0.058 mmol), sodium hydrogen carbonate(13.5 mg, 0.16 mmol) and dichloro-bis(triphenylphosphine)palladium (II)(2.2 mg, 0.0031 mmol) was added toluene (1.25 mL) followed by ethanol(0.75 mL) and then distilled water (0.35 mL). The reaction mixture wasthen heated in a microwave at 120° C. (300 W) for 1 h, and wassubsequently cooled to rt; the mixture was then partitioned betweenCH₂Cl₂ (40 mL) and water (40 mL), and the organic layer was separated,dried (MgSO₄) and concentrated in vacuo. Purification by flash columnchromatography on silica (eluant 70-90% EtOAc/Hex) furnished C (4.81 mg,0.012 mmol, 24%) as a pale green solid.

¹H NMR (400 MHz, 19:1 CDCl₃/CD₃OD) δ_(H): 8.84 (dd, J=8.0, 1.5 Hz, 1H),8.81 (dd, J=4.8, 1.8 Hz, 1H), 8.36 (d, J=5.5 Hz, 1H), 8.25 (d, J=5.0 Hz,1H), 7.50-7.60 (m, 3H), 4.09-4.16 (m, 4H), 3.92-3.98 (m, 4H).

MS (ES⁺) 389 (100%, [M+H]⁺).

Example D4-Morpholin-4-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine

i. 3-Amino-furo[2,3-b]pyridine-2-carboxylic acid ethyl ester, 2

2-Chloro-3-pyridinecarbonitrile, 1, (4.00 g, 28.9 mmol), Cs₂CO₃ (28.2 g,86.6 mmol) and ethyl glycolate (3 mL, 31.7 mmol) were placed in a flaskunder Ar(g). Dry NMP was added, and the suspension was heated at 75° C.for 20 h with vigorous stirring. The reaction mixture was cooled to rtwhereupon water (200 mL) and Et₂O (3×100 mL) were added. The organiclayers were combined, washed with water (3×15 mL) before being dried(MgSO₄) and concentrated in vacuo. Purification by flash columnchromatography on silica (eluant 15-40% EtOAc/Hex) gave 2 (2.41 g, 11.7mmol, 40%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.51 (dd, J=5.0, 2.0 Hz, 1H), 7.96 (dd,J=8.0, 2.0 Hz, 1H), 7.23-7.28 (m, 1H), 4.44 (q, J=7.0 Hz, 2H), 4.01 (br.s., 2H), 1.44 (t, J=7.0 Hz, 3H).

MS (ES⁺) 229 (100%, [M+Na]⁺).

ii. 1H-Pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine-2,4-dione, 3

Under Ar(g) and at 0° C. to a solution of compound 2 (1.189 g, 5.77mmol) in CH₂Cl₂ (20 mL) was added dropwise chlorosulfonyl isocyanate(0.55 mL, 6.34 mmol). The reaction mixture was allowed to warm to rt,and after 4 h it was concentrated in vacuo. Water (20 mL) was added, andthe suspension was stirred vigorously while heating to 70° C. for 10min. The mixture was then cooled and filtered, washing with water. Theresulting solid cake (0.87 g) was subsequently suspended in water (61mL) and NaOH (3.15 g) was added. After 1 h stirring, LCMS analysisconfirmed that the reaction had gone to completion. The mixture was thenfiltered, washing with water, to furnish 3 (460 mg, 2.3 mmol, 40%) as awhite solid.

¹H NMR (400 MHz, DMSO-d₆) δ_(H): 12.06 (br. s., 1H), 11.49 (br. s., 1H),8.60 (dd, J=5.0, 1.5 Hz, 1H), 8.43 (dd, J=8.0, 2.0 Hz, 1H), 7.56 (dd,J=8.0, 5.0 Hz, 1H).

MS (ES⁻) 202 (100%, [M−H]⁻).

iii. 2,4-Dichloro-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine, 4

To compound 3 (0.14 g, 0.70 mmol) and PCl₅ (2.4 g, 2.84 mmol) underAr(g) was added POCl₃ (8 mL), and the resulting reaction mixture wasthen heated at reflux for 20 h. After the mixture had been cooled to rtit was poured onto crushed ice (200 mL) with vigorous stirring. Theaqueous phase was then extracted with CH₂Cl₂ (3×50 mL). The combinedorganic layers were subsequently dried (MgSO₄) and concentrated in vacuoto give 4 (66 mg, 0.28 mmol, 40%) as an off-white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.80 (dd, J=5.0, 1.5 Hz, 1H), 8.64 (dd,J=8.0, 2.0 Hz, 1H), 7.61 (dd, J=7.5, 5.0 Hz, 1H).

MS (ES⁺) 240 (100%. [M+H]⁺).

iv. 2-Chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine, 5

To a solution of 4 (64 mg, 0.27 mmol) in dry methanol (10 mL) was addedmorpholine (55 μL, 0.62 mmol) dropwise, and the resulting reaction wasstirred for 2 h at rt. The resulting precipitate was then filtered,washed with water and then a mixture of 5:1 methanol/water, and theremaining solid was dried in vacuo to furnish 5 (50 mg, 0.17 mmol, 64%)as a white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.63 (dd, J=5.0, 2.0 Hz, 1H), 8.52 (dd,J=7.5, 2.0 Hz, 1H), 7.48 (dd, J=7.5, 5.0 Hz, 1H), 4.10-4.23 (m, 4H),3.86-3.91 (m, 4H).

MS (ES⁺) 291 (100%, [M+H]⁺).

v.4-Morpholin-4-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,D

Under Ar(g) to a mixture of compound 5 (20 mg, 0.069 mmol),7-azaindole-4-boronic acid pinacol ester (18.5 mg, 0.076 mmol),dichloro-bis(triphenylphosphine)palladium (II) (2.4 mg, 0.003 mmol) andsodium hydrogen carbonate (17.4 mg, 0.21 mmol) was added ethanol (1 mL)followed by toluene (1.6 mL) and then water (0.5 mL). The reactionmixture was then heated in a microwave at 120° C. (300 W) for 1 h, andwas subsequently cooled to rt; the mixture was then partitioned betweenCH₂Cl₂ and water, and the organic layer was separated, dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatography onsilica (eluant 30-90% EtOAc/Hex) furnished D (20 mg, 0.054 mol, 78%) asan off-white solid.

¹H NMR (400 MHz, 9:1 CDCl₃/CD₃OD) δ_(H): 8.61 (dd, J=7.5, 1.5 Hz, 1H),8.54 (dd, J=5.0, 1.5 Hz, 1H), 8.28 (d, J=5.0 Hz, 1H), 8.00 (d, J=5.0 Hz,1H), 7.46 (dd, J=7.5, 5.0 Hz, 1H), 7.41 (d, J=3.5 Hz, 1H), 7.32 (d,J=3.5 Hz, 1H), 4.15-4.24 (m, 4H), 3.84-3.92 (m, 4H).

MS (ES⁺) 373 (100%, [M+H]⁺).

Example E2,8-Bis-(1H-indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine

i. 3-Amino-5-bromo-furo[2,3-b]pyridine-2-carboxylic acid ethyl ester, 2

5-Bromo-2-chloro-3-pyridinecarbonitrile, 1, (4.802 g, 22.08 mmol),Cs₂CO₃ (21.6 g, 66.2 mmol) and ethyl glycolate (2.3 mL, 24.3 mmol) wereplaced in a flask under Ar(g). Dry NMP (50 mL) was added, and thesuspension was heated at 75° C. for 20 h with vigorous stirring. Thereaction mixture was cooled to rt whereupon water (200 mL) and Et₂O(3×100 mL) were added. The organic layers were combined, washed withwater (3×15 mL) before being dried (MgSO₄) and concentrated in vacuo.Purification by flash column chromatography on silica (eluant 15-25%EtOAc/Hex) gave 2 (1.701 g, 5.97 mmol, 27%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.53 (d, 1H), 8.07 (d, J=2.0 Hz, 1H),5.00 (br. s., 2H), 4.44 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H).

MS (ES⁺) 309 (100%, [M+Na]⁺), 307 (100%, [M+Na]⁺).

ii. 8-Bromo-1H-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine-2,4-dione, 3

Under Ar(g) and at 0° C. to a solution of compound 2 (1.701 g, 5.97mmol) in CH₂Cl₂ (70 mL) was added dropwise chlorosulfonyl isocyanate(0.62 mL, 7.16 mmol). The reaction mixture was allowed to warm to rt andafter 2.5 h it was concentrated in vacuo. Water (140 mL) was added, andthe suspension was stirred vigorously while heating to 70° C. for 1 h[MS analysis showed formation of the urea intermediate was complete].The mixture was then cooled to rt whereupon NaOH (5.6 g [to give a 1Msolution]) was added. After 25 min a yellow/white precipitate hadformed, 1M HCl was added to the suspension till pH 5 was achievedwhereupon the mixture was filtered, washing with water, to furnish 3(1.418 g, 5.03 mmol, 84%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ_(H): 12.01 (br. s., 1H), 11.58 (br. s, 1H),8.72 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H).

MS (ES⁻) 282 (100%, [M−H]⁻), 280 (100%, [M−H]⁻).

iii. 2,4-Dichloro-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine, 4

To compound 3 (0.615 g, 2.18 mmol) and PCl₅ (7.2 g, 34.6 mmol) underAr(g) was added POCl₃ (24 mL), and the resulting reaction mixture wasthen heated at reflux for 24 h. After the mixture had been cooled to rtit was poured onto crushed ice (400 mL) with vigorous stirring. Theaqueous phase was then extracted with CH₂Cl₂ (3×100 mL). The combinedorganic layers were subsequently dried (MgSO₄) and concentrated in vacuoto give a 1:1 mixture of 4 and an impurity (0.532 g) as an off-whitesolid that was used directly in the next step.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.78 (d, J=2.5 Hz, 1H), 8.72 (d, J=2.5Hz, 1H), 8.71 (d, J=2.5 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H).

iv.8-Bromo-2-chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,5

To a solution of 4 (532 mg) in dry methanol (25 mL) was added morpholine(321 μL, 3.7 mmol) dropwise, and the resulting reaction was stirred for1 h at rt. The resulting precipitate was then filtered, washed withwater and dried in vacuo to furnish 5 (251 mg, 0.68 mmol, 31%, 2 steps)as a white solid.

¹H NMR (400 MHz. CDCl₃) δ_(H): 8.66 (d, J=2.0 Hz, 1H), 8.62 (d, J=2.0Hz, 1H), 4.07-4.21 (m, 4H), 3.85-3.91 (m, 4H).

MS (ES⁺) 393 (100%, [M+Na]⁺), 391 (80%, [M+Na]⁺).

v.2,8-Bis-(1H-indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,E

Under Ar(g) to a mixture of compound 5 (8 mg, 0.022 mmol),indole-4-boronic acid (10.5 mg, 0.065 mmol),dichloro-bis(triphenylphosphine)palladium (II) (1.5 mg, 0.002 mmol) andsodium hydrogen carbonate (8 mg, 0.097 mmol) was added ethanol (1 mL)followed by toluene (1.6 mL) and then water (0.5 mL). The reactionmixture was then heated in a microwave at 120° C. (300 W) for 1 h, andwas subsequently cooled to rt; the mixture was then partitioned betweenCH₂Cl₂ and water, and the organic layer was separated, dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatography onsilica (eluant 20-40% EtOAc/Hex) furnished E (2.7 mg, 0.005 mol, 25%) asa yellow solid.

¹H NMR (400 MHz, 9:1 CDCl₃/CD₃OD) δ_(H): 9.08 (s, 1H), 8.88 (d, J=1.5Hz, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.43 (d, J=7.5Hz, 1H), 7.17-7.33 (m, 6H), 6.66 (d, J=3.0 Hz, 1H), 4.22-4.31 (m, J=4.5Hz, 4H), 3.85-3.95 (m, 4H).

MS (ES⁺) 487 (100%, [M+H]⁺).

Example F(E)-1-(4-Methyl-piperazin-1-yl)-3-[4-morpholin-4-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-yl]-propenone

i. 1-(4-Methyl-piperazin-1-yl)-propenone, 6

At 0° C. to a solution of N-methylpiperazine (3 mL, 27 mmol) in CH₂Cl₂(15 mL) was added acryloyl chloride (879 mL, 10.8 mmol) dropwise underAr(g). After 2 h water (20 mL) was added. The organic layer wasseparated and washed with water (2×10 mL), dried (MgSO₄), before beingconcentrated in vacuo to give 6 (463 mg, 3 mmol, 28%) as a pale yellowoil that required no further purification.

¹H NMR (400 MHz, CDCl₃) δ_(H): 6.56 (dd, 10.5 Hz, 1H), 6.28 (dd, J=16.6,2.0 Hz, 1H), 5.61-5.75 (m, 1H), 3.54-3.79 (m, 4H), 2.38-2.49 (m, 4H),2.33 (s, 3H).

MS (ES⁺) 155 (100%, [M+H]⁺).

ii.(E)-3-(2-Chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-yl)-1-(4-methyl-piperazin-1-yl)-propenone,7

To a sealed tube was added 5 (as per Example E above, 50 mg, 0.14 mmol),6 (20.9 mg, 0.14 mmol), dichloro-bis(triphenylphosphine)palladium (II)(2.9 mg, 0.004 mmol), XPhos (3.9 mg, 0.008 mmol) and NaOAc (33 mg, 0.41mmol) followed by anhydrous DMF (4 mL) under Ar(g). The lid was sealedand the tube was heated to 11000 for 16 h whereupon it was cooled to rtand diluted with EtOAc (40 mL). The organic layer was washed with water(2×20 mL); the combined aqueous layers were then extracted with CH₂Cl₂(3×60 mL). The combined organic layers were then dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatography onsilica (eluant 2-6% MeOH/CH₂Cl₂) furnished 7 (44 mg, 0.10 mol, 71%) as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.62-8.76 (m, 2H), 7.82 (d, J=15.6 Hz,1H), 7.05 (d, J=15.6 Hz, 1H), 4.07-4.23 (m, 4H), 3.85-3.92 (m, 4H),3.68-3.84 (m, 4H), 2.47-2.61 (m, 4H), 2.39 (s, 3H).

MS (ES⁺) 443 (100%, [M+H]⁺).

iii.(E)-1-(4-Methyl-piperazin-1-yl)-3-[4-morpholin-4-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-yl]-propenone,F

To a sealed tube was added 7 (20 mg, 0.045 mmol), indole-4-boronic acid(18 mg, 0.11 mmol), dichloro-bis(triphenylphosphine)palladium (II) (6.3mg, 0.009 mmol) and Na₂CO₃ (9.6 mg, 0.09 mmol) followed by dioxane (2mL) and water (0.8 mL) under Ar(g). The lid was sealed and the tube washeated to 88° C. for 20 h whereupon it was cooled to rt and diluted withEtOAc (30 mL) and 50% brine (5 mL). The organic layer was separated andthe aqueous layer extracted with EtOAc (3×15 mL). The combined organiclayers were then dried (MgSO₄) and concentrated in vacuo. Purificationby flash column chromatography on silica (eluant 2-5% MeOH/CH₂Cl₂)furnished F (6.8 mg, 0.013 mol, 29%) as a white solid.

¹H NMR (400 MHz, 5:1 CDCl₃/CD₃OD) δ_(H): 8.74 (d, J=2.0 Hz, 1H), 8.54(d, J=2.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.65 (d, J=15.1 Hz, 1H), 7.40(d, J=8.0 Hz, 1H), 7.18-7.25 (m, 2H), 7.14 (t, J=7.7 Hz, 1H), 7.05 (d,J=15.1 Hz, 1H), 4.08-4.13 (m, 4H), 3.75-3.82 (m, 4H), 3.61-3.73 (m, 4H),2.37-2.55 (m, 4H), 2.27 (s, 3H).

MS (ES⁺) 524 (100%, [M+H]⁺).

Example G(E)-3-[2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-yl]-N,N-dimethylacrylamide

i.(E)-3-(2-Chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-yl)-N,N-dimethylacrylamide,7

To a sealed tube was added 5 (as per Example E above, 50 mg, 0.14 mmol),dimethylacrylamide (6, 14 mL, 0.14 mmol),dichloro-bis(triphenylphosphine)palladium (II) (2.8 mg, 0.004 mmol),XPhos (3.9 mg, 0.008 mmol) and NaOAc (33 mg, 0.41 mmol) followed byanhydrous DMF (3.5 mL) under Ar(g). The lid was sealed and the tube washeated to 110° C. for 16 h whereupon it was cooled to rt and dilutedwith EtOAc (40 mL) The organic layer was washed with 50% brine (3×10 mL)then dried (MgSO₄) and concentrated in vacuo. Purification by flashcolumn chromatography on silica (eluant 50-100% EtOAc/Hex then 1% MeOH)furnished 7 (44 mg, 0.11 mol, 84%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.70 (s, 2H), 7.82 (d, J=15.6 Hz, 1H),7.07 (d, J=15.6 Hz, 1H), 4.11-4.19 (m, 4H), 3.85-3.93 (m, 4H), 3.22 (s,3H), 3.11 (s, 3H).

MS (ES⁺) 388 (100%, [M+H]⁺).

ii.(E)-3-[2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-yl]-N,N-dimethylacrylamide,G

To a sealed tube was added 7 (30 mg, 0.077 mmol), indole-4-boronic acid(31 mg, 0.19 mmol), dichloro-bis(triphenylphosphine)palladium (II) (13.6mg, 0.02 mmol) and Na₂CO₃ (24.4 mg, 0.23 mmol) followed by dioxane (3mL) and water (1.2 mL) under Ar(g). The lid was sealed and the tube washeated to 88° C. for 20 h whereupon it was cooled to rt and diluted withEtOAc (30 mL) and 50% brine (3 mL). The organic layer was separated andthe aqueous layer extracted with EtOAc (2×5 mL). The combined organiclayers were then dried (MgSO₄) and concentrated in vacuo. Purificationby flash column chromatography on silica (eluant 1-3% MeOH/CH₂Cl₂)furnished G (6.9 mg, 0.015 mol, 19%) as an off white solid.

¹H NMR (400 MHz, 5:1 CDCl₃/CD₃OD) δ_(H): 8.77 (d, J=2.0 Hz, 1H), 8.55(d, J=2.0 Hz, 1H), 7.88 (dd, J=7.5, 1.0 Hz, 1H), 7.61 (d, J=15.6 Hz,1H), 7.40 (d, J=8.0 Hz, 1H), 7.21 (d, J=3.0 Hz, 1H), 7.10-7.17 (m, 2H),7.04 (d, J=15.6 Hz, 1H), 4.09 (s, 4H), 3.74-3.82 (m, 4H), 3.11 (s, 3H),2.94 (s, 3H).

MS (ES⁺) 469 (100%, [M+H]⁺).

Example H[2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl]-dimethyl-amine

i.2-Chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine-8-carbaldehyde,8

To a solution of(E)-3-(2-chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-yl)-N,N-dimethylacrylamide(7, as per Example G above) (13 mg, 0.034 mmol) in THF (1.5 mL) wasadded H₂O (0.5 mL) followed by NaIO₄ (22 mg, 0.10 mmol) and a solutionof OsO₄ (2.5% wt/v in ^(t)BuOH, 9 mL, 0.0009 mmol) under Ar(g). Afterstirring for 2 days at rt, EtOAc (25 mL) and sodium thiosulfate (0.1M, 5mL) were added. The organic layer was separated and washed with brine (3mL) before being dried (MgSO₄) and concentrated in vacuo. Purificationby flash column chromatography on silica (eluant 5-20% EtOAc/CH₂Cl₂)furnished 8 (8 mg, 0.025 mmol, 74%) as a white solid.

¹H NMR (9:1 CDCl₃/CD₃OD) δ_(H): 10.13 (s, 1H), 9.04 (d, J=2.0 Hz, 1H),8.91 (d, J=2.0 Hz, 1H), 3.99-4.13 (m, 4H), 3.73-3.84 (m, 4H).

LCMS (ES⁺) 351 (100%, [M+MeOH+H]⁺), 319 (40%, [M+H]⁺).

ii.(2-Chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl)-dimethyl-amine,9

To a suspension of 8 (7.8 mg, 0.024 mmol) in dry DMF (2.5 mL) was addeda solution of dimethylamine (2M in MeOH, 24 mL, 0.049 mmol) followed byNaBH(OAc)₃ (8 mg, 0.037 mmol) under Ar(g). After stirring at rt for 23h, a further quantity of dimethylamine (2M in MeOH, 35 mL, 0.071 mmol)and NaBH(OAc)₃ (6 mg, 0.028 mmol) were added. After 3 days the reactionwas concentrated in vacuo. EtOAc (40 mL) and 50% saturated brine (5 mL)were added and the organic layer separated, re-extracting the aqueouswith EtOAc (2×15 mL). The combined organic layers were then dried(MgSO₄) and concentrated in vacuo. Purification by flash columnchromatography on silica (eluant 1-6% MeOH/CH₂Cl₂) furnished 9 (5 mg,0.014 mmol, 60%) as a white solid.

¹H NMR (CDCl₃) δ_(H): 8.65 (d, J=2.0 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H),4.08-4.23 (m, 4H), 3.82-3.93 (m, 4H), 3.75 (br. s., 2H), 2.38 (s, 6H).

MS (ES⁺) 348 (100%, [M+H]⁺).

iii.[2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl]-dimethyl-amine,H

To a sealed tube was added 9 (5 mg, 0.014 mmol), indole-4-boronic acid(5.8 mg, 0.036 mmol), dichloro-bis(triphenylphosphine)palladium (II)(2.0 mg, 0.0029 mmol) and Na₂CO₃ (3.1 mg, 0.029 mmol) followed bydioxane (2 mL) and water (0.8 mL) under Ar(g). The lid was sealed andthe tube was heated to 88° C. for 18 h whereupon it was cooled to rt anddiluted with EtOAc (35 mL) and 50% saturated brine (5 mL). The organiclayer was separated and the aqueous layer extracted with EtOAc (2×10mL). The combined organic layers were then dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatography onsilica (eluant 2-5% MeOH/CH₂Cl₂) furnished H (2 mg, 0.005 mmol, 32%) asan off-white solid.

¹H NMR (400 MHz, 9:1 CDCl₃/CD₃OD) δ_(H): 9.79 (br. s., 1H), 8.57 (br. s,1H), 8.53 (br. s., 1H), 7.98 (d, J=7.5 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H),7.24-7.32 (m, 2H), 7.19 (t, J=8.0 Hz, 1H), 4.13-4.19 (m, 4H), 3.81-3.87(m, 4H), 3.78 (br. s, 2H), 2.36 (s, 6H).

MS (ES⁺) 429 (100%, [M+H]⁺).

Example I2-(1H-Indol-4-yl)-4-morpholin-4-yl-8-piperidin-1-ylmethyl-pyrido[3′,2′:4,5]furo[3,2d]pyrimidine

i.2-Chloro-4-morpholin-4-yl-8-piperidin-1-ylmethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,10

To compound 8 (as per Example H above) (19.7 mg, 0.062 mmol) in dry DMF(6.3 mL) was added piperidine (12.2 μL, 0.14 mmol) followed byNaBH(OAc)₃ (20.05 mg, 0.095 mmol) and the reaction was stirred for 5 h.After which time NaBH₃CN (5.8 mg, 0.092 mmol) was added and the reactionwas stirred for a further 48 h. The DMF was removed in vacuo, EtOAc (50mL) was added along with 50% saturated brine (50 mL), the layersseparated, extracted with EtOAc (2×30 mL), dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatography onsilica (eluant 0:1-6:94) MeOH/CH₂Cl₂) furnished 10 (12.9 mg, 0.033 mmol,54%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.55 (d, J=2.0 Hz, 1H), 8.49 (d, J=2.0Hz, 1H), 4.15 (br. s., 4H), 3.84-3.90 (m, 4H), 3.65 (s, 2H), 2.42 (m,4H), 1.59 (quin, J=5.5 Hz, 4H), 1.41-1.49 (m, 2H).

MS (ES⁺) 388.2 (100%, [M+H]⁺).

ii.2-(1H-Indol-4-yl)-4-morpholin-4-yl-8-piperidin-1-ylmethyl-pyrido[3′,2′:4,5]furo[3,2d]pyrimidine,I

To indole-4-boronic acid (13.4 mg, 0.083 mmol),dichloro-bis(triphenylphosphine)palladium (II) (4.60 mg, 0.0065 mmol)and sodium carbonate (7.22 mg, 0.068 mmol) was added compound 10 (12.9mg, 0.033 mmol) dissolved in dioxane/water (2 mL/0.8 mL). The reactionwas then heated in a sealed tube at 88° C. for 16 h. The reaction wascooled to rt where the reaction was partitioned between EtOAc/water (30mL/5 mL) and the layers were separated, extracted with EtOAc (3×10 mL),dried (MgSO₄) and concentrated in vacuo. Purification by flash columnchromatography on silica (eluant 0:1-6:94) MeOH/CH₂Cl₂) give I (4 mg,0.0085 mol, 26%) as a white solid.

¹H NMR (400 MHz, 9.5:0.5 CDCl₃/CD₃OD) δ_(H): 8.59 (d, J=2.0 Hz, 1H),8.50 (d, J=2.5 Hz, 1H), 8.12 (d, J=7.5 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H),7.45-7.47 (m, 1H), 7.33 (d, J=3.0 Hz, 1H), 7.25-7.30 (m, 2H), 4.22 (t,J=4.9 Hz, 4H), 3.87-3.92 (m, 4H), 3.67 (s, 2H), 2.44 (m, 4H), 1.54-1.62(m, 4H), 1.39-1.46 (m, 2H).

MS (ES⁺) 469.2 (100%, [M+H]⁺).

Example J2-(1H-Indol-4-yl)-8-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine

i.2-Chloro-8-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,11

To compound 8 (as per Example H above) (19.13 mg, 0.060 mmol) in dryCH₂Cl₂ (6.6 mL) was added N-methylpiperazine (133 μL, 0.12 mmol)followed by NaBH₃CN (4.6 mg, 0.073 mmol) and the reaction mixture wasstirred for 21 h. NaBH(OAc)₃ (11.3 mg, 0.053 mmol) was then added andthe reaction mixture was stirred for a further 6.5 h. EtOAc (50 mL) wasadded along with 50% saturated brine (50 mL); the layers were separated,extracted with EtOAc (2×30 mL), dried over MgSO₄, and concentrated invacuo. Purification by flash column chromatography on silica (eluant0:1-1:9 MeOH/CH₂Cl₂) furnished 11 (8.48 mg, 0.021 mmol, 35%) as a whitesolid.

¹H NMR (400 MHz, 9:1 CDCl₃/CD₃OD) δ_(H): 8.49 (d, J=2.5 Hz, 1H), 8.45(d, J=2.0 Hz, 1H), 4.10 (br. s., 4H), 3.82 (t, J=4.8 Hz, 4H), 3.65 (s,2H), 2.49 (br. s., 8H, 2.27 (s, 3H), MS (ES⁺) 403.1 (100%, [M+H]⁺).

ii.2-(1H-Indol-4-yl)-8-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,J

To indole-4-boronic acid (14.1 mg, 0.088 mmol),dichloro-bis(triphenylphosphine)palladium (II) (4.77 mg, 0.0068 mmol)and sodium carbonate (7.47 mg, 0.070 mmol) was added compound 11 (13.1mg, 0.032 mmol) dissolved in dioxane/water (2 mL/0.8 mL). The resultingreaction mixture was then heated in a sealed tube at 88° C. for 16 h.The mixture was then cooled to rt, and was partitioned betweenEtOAc/water (30 mL/5 mL); the layers were subsequently separated,extracted with EtOAc (2×10 mL), dried (MgSO₄) and concentrated in vacuo.Purification by flash column chromatography on silica (eluant 0:1-1:9)MeOH/CH₂Cl₂) furnished compound J (3.97 mg, 0.0082 mol, 25%) as a whitesolid.

¹H NMR (400 MHz, 9:1 CDCl₃/CD₃OD) δ_(H): 8.59 (d, J=2.0 Hz, 1H), 8.48(d, J=2.0 Hz, 1H), 8.06-8.12 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.42 (d,J=3.0 Hz, 1H), 7.32 (d, J=3.0 Hz, 1H), 7.25 (s, 1H), 4.20 (t, J=4.8 Hz,4H), 3.88 (m, J=4.8 Hz, 4H), 3.67 (s, 2H), 2.51 (br. s., 8H), 2.25 (s,3H).

MS (E⁺) 484.2 (100%, [M+H]⁺).

Example K2-(1H-Indol-4-yl)-4-morpholin-4-yl-8-morpholin-4-ylmethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine

i.2-Chloro-4-morpholin-4-yl-8-morpholin-4-ylmethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,12

To compound 8 (as per Example H above) (19.7 mg, 0.062 mmol) in dry DMF(3 mL) was added morpholine (11 μL, 0.13 mmol) followed by NaBH(OAc)₃(20 mg, 0.095 mmol) under Ar(g) and the reaction mixture was stirred for3 days. NaBH₃CN (5 mg, 0.07 mmol) was then added, and the reactionmixture was stirred for a further 5 h. The DMF was then removed invacuo, and EtOAc (40 mL) was added along with 50% saturated brine (5mL); the resulting layers were separated, extracted with EtOAc (2×15mL), dried (MgSO₄) and concentrated in vacuo. Purification by flashcolumn chromatography on silica (eluant 1-2.5% MeOH/CH₂Cl₂) furnished 12(15 mg, 0.038 mmol, 61%) as a white solid.

¹H NMR (CDCl₃) δ_(H): 8.56 (s, 1H), 8.53 (s, 1H), 4.08-4.21 (m, 4H),3.83-3.91 (m, 4H), 3.65-3.79 (m, 6H), 2.43-2.59 (m, 4H).

MS (ES⁺) 390 (100%, [M+H]⁺).

ii.2-(1H-Indol-4-yl)-4-morpholin-4-yl-8-morpholin-4-ylmethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,K

To a sealed tube was added compound 12 (15 mg, 0.038 mmol),indole-4-boronic acid (15.5 mg, 0.1 mmol),dichloro-bis(triphenylphosphine)palladium (II) (5.4 mg, 0.008 mmol) andNa₂CO₃ (8.2 mg, 0.077 mmol), followed by dioxane (2 mL) and water (0.8mL) under Ar(g). The tube was heated to 88° C. for 18 h whereupon it wascooled to rt, and diluted with EtOAc (35 mL) and 50% saturated brine (5mL). The organic layer was separated and the aqueous layer extractedwith EtOAc (2×10 mL). The combined organic layers were then dried(MgSO₄) and concentrated in vacuo. Purification by flash columnchromatography on silica (eluant 1-3% MeOH/CH₂Cl₂) furnished K (6.7 mg,0.014 mmol, 37%) as an off-white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.63 (d, J=2.0 Hz, 1H), 8.58 (br. s.,1H), 8.39 (br. s., 1H), 8.24 (dd, J=7.5, 1.0 Hz, 1H), 7.58-7.67 (m, 1H),7.53 (d, J=8.0 Hz, 1H), 7.38 (t, J=2.5 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H),4.19-4.33 (m, 4H), 3.90-4.01 (m, 4H), 3.67-3.84 (m, 6H), 2.45-2.67 (m,4H).

MS (ES⁺) 471 (100%, [M+H]⁺).

Example L[2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl]-(2-methoxy-ethyl)-methyl-amine

i.(2-Chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl)-(2-methoxy-ethyl)-methyl-amine,13

To compound 8 (as per Example H above) (23 mg, 0.072 mmol) in dry CH₂Cl₂(5 mL), MeOH (2 mL) was added 3 Å molecular sieves,(2-methoxyethyl)methylamine (12 μL, 0.11 mmol) followed by NaBH(OAc)₃(46 mg, 0.22 mmol) and NaBH₃CN (4.5 mg, 0.07 mmol) under Ar(g). After 18h, the reaction mixture was filtered, washing through with CH₂Cl₂ (30mL). 50% saturated brine (5 mL) was then added to the filtrate and thelayers were separated, extracting with CH₂Cl₂ followed by EtOAc, dried(MgSO₄) and concentrated in vacuo. Purification by first flash columnchromatography on silica (eluant 1-4% MeOH/CH₂C)₂) followed by ionexchange column chromatography (SCX-3, MeOH-0.5M NH₃ in MeOH) furnished13 (11 mg, 0.028 mmol, 39%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.60 (d, J=2.0 Hz, 1H), 8.49 (d, J=2.0Hz, 1H), 4.10-4.19 (m, 4H), 3.84-3.90 (m, 4H), 3.80 (br. s., 2H), 3.57(t, J=5.5 Hz, 2H), 3.37 (s, 3H), 2.71 (t, J=5.5 Hz, 2H), 2.31 (s, 3H).

MS (ES⁺) 392 (100%, [M+H]⁺).

ii.[2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl]-(2-methoxy-ethyl)-methyl-amine,L

To a sealed tube was added compound 13 (11 mg, 0.028 mmol),indole-4-boronic acid (11.3 mg, 0.07 mmol),dichloro-bis(triphenylphosphine)palladium (II) (4 mg, 0.006 mmol) andNa₂CO₃ (6 mg, 0.056 mmol) followed by dioxane (2 mL) and water (0.8 mL)under Ar(g). The tube was heated to 88° C. for 18 h whereupon it wascooled to rt and diluted with EtOAc (35 mL) and 50% saturated brine (5mL). The organic layer was separated and the aqueous layer extractedwith EtOAc (2×10 mL). The combined organic layers were then dried(MgSO₄) and concentrated in vacuo. Purification by flash columnchromatography on silica (eluant 1-3% MeOH/CH₂Cl₂) furnished L (4.5 mg,0.01 mmol, 34%) as an off-white solid.

¹H NMR (400 MHz, 9:1 CDCl₃/CD₃OD) δ_(H): 9.80 (br. s., 1H), 8.56 (s,1H), 8.49 (br. s., 1H), 7.98 (d, J=7.5 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H),7.31 (br. s., 1H), 7.24-7.28 (m, 1H), 7.18 (t, J=7.5 Hz, 1H), 4.10-4.20(m, 4H), 3.76-3.87 (m, 4H), 3.51 (t, J=5.0 Hz, 2H), 3.27 (s, 3H),3.22-3.26 (m, 2H), 2.59-2.75 (m, 2H), 2.29 (s, 3H). MS (ES⁺) 473 (100%,[M+H]⁺).

Example M2-(1H-Indol-4-yl)-4,8-di-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine

i.2-Chloro-4,8-di-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,14

To a sealed tube was added compound 5 (as per Example E above, 20 mg,0.054 mmol), Pd₂(dba)₃ (1.5 mg, 0.0016 mmol), ±BINAP (2 mg, 0.0032 mmol)and Cs₂CO₃ (26 mg, 0.081 mmol) followed by dry toluene (2 mL) andmorpholine (5.7 mL, 0.065 mmol) under Ar(g). The tube was heated at 90°C. for 18 h. After cooling to rt, EtOAc (35 mL) and 50% saturated brine(5 mL) were added. The organic layer was separated and the aqueous layerextracted with EtOAc (2×10 mL). The combined organic layers were thendried (MgSO₄) and concentrated in vacuo. Purification by flash columnchromatography on silica (eluant 0.5-2% MeOH/CH₂Cl₂) furnished 14 (10mg, 0.027 mmol, 49%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.34 (d, J=3.0 Hz, 1H), 7.94 (d, J=3.0Hz, 1H), 4.07-4.23 (m, 4H), 3.90-3.97 (m, 4H), 3.81-3.89 (m, 4H),3.18-3.28 (m, 4H).

MS (ES⁺) 376 (100%, [M+H]⁺).

ii.2-(1H-Indol-4-yl)-4,8-di-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,M

To a sealed tube was added compound 14 (10 mg, 0.027 mmol),indole-4-boronic acid (10.9 mg, 0.068 mmol),dichloro-bis(triphenylphosphine)palladium (II) (3.7 mg, 0.005 mmol) andNa₂CO₃ (5.7 mg, 0.054 mmol) followed by dioxane (2 mL) and water (0.8mL) under Ar(g). The tube was heated to 88° C. for 18 h whereupon it wascooled to rt and diluted with EtOAc (35 mL) and 50% saturated brine (5mL). The organic layer was separated and the aqueous layer extractedwith EtOAc (2×10 mL). The combined organic layers were then dried(MgSO₄) and concentrated in vacuo. Purification by first flash columnchromatography on silica (eluant 0.5-1.5% MeOH/CH₂Cl₂) followed by ionexchange column chromatography (SCX-3, MeOH-0.5M NH₃ in MeOH) furnishedM (3.2 mg, 0.007 mmol, 26%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.39 (br. s., 1H), 8.35 (d, J=2.5 Hz,1H), 8.21 (d, J=7.5 Hz, 1H), 7.33-7.58 (m, 3H), 7.19-7.31 (m, 2H),4.19-4.37 (m, 4H), 3.85-4.02 (m, 8H), 3.25-3.37 (m, 4H).

LCMS (ES⁺) 457 (100%, [M+H]⁺).

Example N2-(1H-Indol-4-yl)-7-methyl-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine

i. 3-Amino-6-methyl-fu o[2,3-b]pyridine-2-carboxylic acid ethyl ester,16

To a suspension of 2-chloro-3-cyano-6-methylpyridine, 15 (2.0 g, 13.1mmol, 1 eq) and cesium carbonate (12.8 g, 393 mmol, 3 eq) in anhydrousNMP (20 mL) was added at rt ethyl glycolate (1.36 mL, 14.4 mmol, 1.1 eq)under Ar(g). The reaction mixture was heated up at 75° C. overnight:once cooled down, it was partitioned with H₂O (200 mL) and extractedwith EtOAc (3×70 mL). The combined organics were thoroughly washed withH₂O (3×75 mL), than dried over MgSO₄ and the solvent was removed invacuo. The residue was further purified by silica gel columnchromatography with hexane/EtOAc (4:1-1:3) to yield 16 as a pale yellowsolid (1.30 g, 45%).

¹H NMR (400 MHz, CDCl₃) δ_(H): 7.84 (d, J=8.0 Hz, 1H). 7.12 (d, J=8.0Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 4.26 (br. s., 2H), 2.66 (s, 3H), 1.42(t, J=7.0 Hz, 3H).

MS (ES⁺) 221.0 (50%, [M+H]⁺), 243.0 (50%, [M+Na]⁺).

ii. 7-Methyl-1H-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine-2,4-dione, 17

A round-bottomed flask was loaded up with3-amino-6-methyl-furo[2,3-b]pyridine-2-carboxylic acid ethyl ester, 16(926 mg, 4.20 mmol, 1 eq) and urea (2.52 g, 42.0 mmol, 10 eq). Themixture was heated up at 190° C. for 3 h until no more ammonia releasewas observed. H₂O (10 mL) was added, and the reaction mixture wasstirred for 30 min vigorously; it was then filtered, and the solid waswashed with H₂O (3×10 mL) before drying to furnish the product as a palebrown solid (1.60 g, quant.)

¹H NMR (400 MHz, DMSO-d₆) δ_(H): 8.24 (d, J=7.5 Hz, 1H), 7.40 (d, J=8.0Hz, 1H), 7.16 (br. s., 1H), 5.41 (br. s., 1H), 2.61 (s, 3H).

MS (ES⁺) 240.0 (100%, [M+Na]⁺).

iii.2-Chloro-7-methyl-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,18

To a mixture of7-methyl-1H-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine-2,4-dione (1.6 g,4.20 mmol, 1 eq) 17, and PCl₅ (10.5 g, 50 mmol, 12 eq) was added at rtPOCl₃ (33.5 mL, 357 mmol, 85 eq) under Ar(g). The reaction mixture wasrefluxed at 115° C. overnight. Once cooled down to rt, the mixture waspoured dropwise very slowly onto stirred crushed ice over 2 h, thenwarmed up to rt for 1 h. The resulting aqueous was extracted with EtOAc(3×100 mL) and CH₂Cl₂ (4×100 mL). The combined organics were dried overMgSO₄ and the solvent was removed in vacuo. To this residue in dry MeOH(50 mL) was added at rt morpholine (0.92 mL, 10.5 mmol, 2.5 eq) underAr(g). The reaction mixture was stirred for 3 h, then the solvent wasremoved in vacuo. The residue was further purified by silica gel columnchromatography with hexane/EtOAc (1:1-0:1) to yield the product as apale brown solid (384 mg, 30%).

¹H NMR (400 MHz, CDCl₃) δ_(H): 8.38 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0Hz, 1H), 4.10-4.19 (m, 4H), 3.84-3.89 (m, 4H), 2.74 (s, 3H).

MS (ES⁺) 305.0 (90%, [M+H]⁺).

iv.2-(1H-Indol-4-yl)-7-methyl-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,N

To a solution of2-chloro-7-methyl-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,18 (27 mg, 0.09 mmol, 1 eq), indole-4-boronic acid (43 mg, 0.27 mmol, 3eq) and PdCl₂(PPh₃)₂ (12.4 mg, 0.02 mmol, mol %) in a mixture of dioxane(2 mL) and H₂O (1.0 mL) was added Na₂CO₃ (19 mg, 0.18 mmol, 2 eq) underAr(g). The reaction mixture was then heated in a pressure tube for 18 hat 90° C. Once cooled down, the mixture was partitioned with H₂O (10 mL)and extracted with CH₂Cl₂ (2×10 mL) and EtOAc (2×10 mL). The combinedorganic extracts were dried over MgSO₄ and the solvent was removed invacuo. The residue was further purified by SCX-3 cartridge eluting withCH₂Cl₂/MeOH (1:0-0:1 then +1M NH₃) followed by silica gel columnchromatography with hexane/EtOAc (3:1-0:1) to yield N as a pale brownsolid (5.4 mg, 16%).

¹H NMR (400 MHz, CDCl₃+10% MeOD) δ_(H): 8.38 (d, J=8.0 Hz, 1H), 7.82 (d,J=7.5 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.16 (d,J=3.0 Hz, 1H), 7.12 (m, J=1.0 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 4.03-4.09(m, 4H), 3.70-3.76 (m, 4H), 2.54 (s, 3H).

MS (ES⁺) 386.1 (100%, [M+H]⁺).

Example O8-(4-Fluoro-piperidin-1-ylmethyl)-2-(1H-indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine

i.2-Chloro-8-(4-fluoro-piperidin-1-ylmethyl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,19

To compound 8 (as per Example H above) (80 mg, 0.25 mmol) in dry DMF (12mL) was added 4-fluoropiperidine hydrochloride (70 mg, 0.5 mmol) andNaOAc (41 mg, 0.5 mmol) under Ar(g). After 20 minutes NaBH(OAc)₃ (106mg, 0.5 mmol) and NaBH₃CN (16 mg, 0.25 mmol) were added and thesuspension was stirred for 16 h. The DMF was then removed in vacuo,EtOAc (45 mL) was added along with 50% saturated brine (7 mL), thelayers separated, extracted with EtOAc (2×15 mL), dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatography onsilica (eluant 1-2% MeOH/CH₂Cl₂) furnished 9 (58 mg, 0.014 mmol, 57%) asa white solid.

¹H NMR (300 MHz, CDCl₃) δ_(H): 8.55 (d, J=1.8 Hz, 1H), 8.51 (d, J=1.8Hz, 1H), 4.58-4.86 (m, 1H), 4.06-4.23 (m, 4H), 3.82-3.92 (m, 4H), 3.69(s, 2H), 2.54-2.68 (m, 2H), 2.38-2.52 (m, 2H), 1.81-2.00 (m, 4H).

LCMS (ES⁺) 406 (100%, [M+H]⁺).

ii.8-(4-Fluoro-piperidin-1-ylmethyl)-2-(1H-indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,O

To a sealed tube was added 19 (55 mg, 0.136 mmol), indole-4-boronic acid(55 mg, 0.34 mmol), dichloro-bis(triphenylphosphine)palladium (II) (19mg, 0.027 mmol) and Na₂CO₃ (29 mg, 0.27 mmol) followed by dioxane (3.5mL) and water (1.4 mL) under Ar(g). The tube was heated to 88° C. for 18h whereupon it was cooled to rt and diluted with EtOAc (45 mL) and 50%saturated brine (7 mL). The organic layer was separated and the aqueouslayer extracted with EtOAc (2×10 mL). The combined organic layers werethen dried (MgSO₄) and concentrated in vacuo. Purification by flashcolumn chromatography on silica (eluant 1-3% MeOH/CH₂Cl₂) furnished O(30 mg, 0.06 mmol, 45%) as a brown solid.

¹H NMR (300 MHz, CDCl₃) δ_(H): 8.62 (d, J=2.2 Hz, 1H), 8.55 (d, J=2.2Hz, 1H), 8.34 (br. s., 1H), 8.24 (d, J=7.0 Hz, 1H), 7.59-7.68 (m, 1H),7.54 (d, J=8.1 Hz, 1H), 7.31-7.41 (m, 2H), 4.57-4.88 (m, 1H), 4.20-4.34(m, 4H), 3.89-4.00 (m, 4H), 3.72 (s, 2H), 2.57-2.74 (m, 2H), 2.39-2.54(m, 2H), 1.81-2.04 (m, 4H).

LCMS (ES⁺) 487 (100%, [M+H]⁺).

Example P8-(4,4-Difluoro-piperidin-1-ylmethyl)-2-(1H-indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine

i.8-(4,4-Difluoro-piperidin-1-ylmethyl)-2-(1H-indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,20

To compound 8 (as per Example H above) (80 mg, 0.25 mmol) in dry DMF (12mL) was added 4,4-difluoropiperidine hydrochloride (79 mg, 0.5 mmol) andNaOAc (41 mg, 0.5 mmol) under Ar(g). After 20 minutes NaBH(OAc)₃ (106mg, 0.5 mmol) and NaBH₃CN (16 mg, 0.25 mmol) were added and thesuspension was stirred for 16 h. The DMF was then removed in vacuo,EtOAc (45 mL) was added along with 50% saturated brine (7 mL), thelayers separated, extracted with EtOAc (2×15 mL), dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatography onsilica (eluant 1-2% MeOH/CH₂Cl₂) furnished (41 mg, 0.097 mmol, 39%) as awhite solid.

¹H NMR (300 MHz, CDCl₃) δ_(H): 8.55 (d, J=2.0 Hz, 1H), 8.51 (d, J=2.0Hz, 1H), 4.08-4.23 (m, 4H), 3.82-3.93 (m, 4H), 3.74 (s, 2H), 2.54-2.66(m, 4H), 1.92-2.12 (m, 4H).

LCMS (ES⁺) 424 (100%, [M+H]⁺).

ii.[2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl]-(2-methoxy-ethyl)-methyl-amine,N

To a sealed tube was added 20 (41 mg, 0.097 mmol), indole-4-boronic acid(39 mg, 0.24 mmol), dichloro-bis(triphenylphosphine)palladium (II) (13.6mg, 0.02 mmol) and Na₂CO₃ (21 mg, 0.19 mmol) followed by dioxane (3.5mL) and water (1.4 mL) under Ar(g). The tube was heated to 88° C. for 18h, and the reaction mixture was then cooled to rt, and diluted withEtOAc (45 mL) and 50% saturated brine (7 mL). The organic layer wasseparated and the aqueous layer extracted with EtOAc (2×10 mL). Thecombined organic layers were then dried (MgSO₄) and concentrated invacuo. Purification by flash column chromatography on silica (eluant0.5-2% MeOH/CH₂Cl₂) furnished P (7.4 mg, 0.015 mmol, 15%) as a whitesolid.

¹H NMR (300 MHz, CDCl₃) δ_(H): 8.61 (d, J=2.3 Hz, 1H), 8.54 (d, J=2.3Hz, 1H), 8.38 (br. s., 1H), 8.24 (dd, J=7.5, 0.8 Hz, 1H), 7.58-7.65 (m,1H), 7.53 (d, J=7.9 Hz, 1H), 7.37-7.40 (m, 1H), 7.34 (t, J=7.9 Hz, 1H),4.21-4.32 (m, 4H), 3.91-3.99 (m, 4H), 3.76 (s, 2H), 2.56-2.70 (m, 4H),1.95-2.14 (m, 4H).

LCMS (ES⁺) 505 (100%, [M+H]⁺).

Example Q2-(1H-Indol-4-yl)-8-[4-(2-methoxy-ethyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine

i.2-Chloro-8-[4-(2-methoxy-ethyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,21

To compound 8 (as per Example H above) (22.2 mg, 0.070 mmol) in dryCH₂Cl₂/MeOH (5 mL/2 mL) was added 1-(2-methoxyethyl) piperazine (13 μL,0.093 mmol) and the reaction was stirred for 1 h. NaBH(OAc)₃ (45.8 mg,0.022 mmol) was then added, followed by NaBH₃CN (4.4 mg, 0.070 mmol),and the reaction mixture was stirred for 48 h. EtOAc (30 mL) was addedalong with water/saturated brine (10 mL/5 mL); the layers wereseparated, extracted with EtOAc (2×30 mL), dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatography onsilica (eluant 2:98-6:94 MeOH/CH₂Cl₂) furnished 21 (10 mg, 0.022 mmol,32%) as a white solid.

¹H NMR (300 MHz, 9.5:0.5 CDCl₃/CD₃OD) δ_(H) 8.53 (d, J=1.9 Hz, 1H),8.47-8.52 (m, 1H), 4.14 (br. s., 4H), 3.83-3.93 (m, 4H), 3.68 (s, 2H),3.48-3.57 (m, 2H), 3.34 (s, 3H), 2.47-2.66 (m, 10H). MS (ES⁺) 447.2(100%, [M+H]⁺).

ii.2-(1H-Indol-4-yl)-8-[4-(2-methoxy-ethyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,Q

To indole-4-boronic acid (8.6 mg, 0.053 mmol),dichloro-bis(triphenylphosphine)palladium (II) (3.0 mg, 0.0043 mmol) andsodium carbonate (4.7 mg, 0.045 mmol) was added compound 21 (10.0 mg,0.022 mmol) dissolved in dioxane/water (2 mL/0.8 mL). The reaction wasthen heated in a sealed tube at 88° C. for 16 h, and was subsequentlycooled to rt; it was then partitioned between EtOAc/water (30 mL/5 mL),the layers separated, extracted with EtOAc (2×30 mL), dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatography onsilica (eluant 0:1-2:98 MeOH/CH₂Cl₂) furnished Q (1.09 mg, 0.0021 mol,9%) as a white solid.

LCMS (ES⁺) 528.3 (100%, [M+H]⁺).

Example R3-{4-[2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl]-piperazin-1-yl}-propionitrile

i.3-[4-(2-Chloro-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl)-piperazin-1-yl]-propionitrile,22

To compound 8 (as per Example H above) (24.2 mg, 0.076 mmol) in dryCH₂Cl₂/MeOH (5 mL/2 mL) was added 3-(1-piperazinyl) propionitrile (15μL, 0.11 mmol) and the reaction mixture was stirred for 15 mins.NaBH(OAc)₃ (47.8 mg, 0.023 mmol) was then added, and the resultingmixture was stirred for 17 h. NaBH₃CN (4.8 mg, 0.076 mmol) was added,and following additional stirring for a further 5 h, the reactionmixture was partitioned between EtOAc/water/saturated brine (30 mL/10mL/5 mL), the layers separated, extracted with EtOAc (2×30 mL), dried(MgSO₄) and concentrated in vacuo. Purification using an SCX-2 columnwith MeOH/CH₂Cl₂ (1:9-1:1-1:1+0.2M NH₃ in MeOH) followed by flash columnchromatography on silica (eluant 1:9 MeOH/CH₂Cl₂) furnished 22 (15.1 mg,0.034 mmol, 45%) as a white solid.

¹H NMR (400 MHz, 9:1 CDCl₃/CD₃OD) δ_(H) 8.43 (d, J=2.0 Hz, 1H), 8.38 (d,J=2.0 Hz, 1H), 4.04 (br. s., 4H), 3.76 (t, 4H, J=5.0 Hz), 3.60 (s, 2H),2.57-2.64 (m, 2H), 2.40-2.51 (m, 10H).

MS (ES⁺) 442.1 (100%, [M+H]⁺).

ii.3-{4-[2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl]-piperazin-1-yl}-propionitrile,R

To indole-4-boronic acid (14.6 mg, 0.091 mmol),dichloro-bis(triphenylphosphine)palladium (II) (4.7 mg, 0.0066 mmol) andsodium carbonate (7.5 mg, 0.071 mmol) was added 22 (15.1 mg, 0.034 mmol)dissolved in dioxane/water (2 mL/0.8 mL). The reaction mixture washeated in a sealed tube at 88° C. for 16 h, was subsequently cooled tort, and was then partitioned between EtOAc/water (30 mL/5 mL). Thelayers were separated, extracted with EtOAc (2×30 mL), dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatography onsilica (eluant 2:98-4:96-6:94) MeOH/CH₂Cl₂) furnished R (6.8 mg, 0.013mol, 38%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 8.60 (s, 1H), 8.54 (s, 1H), 8.40 (br. s.,1H), 8.24 (dd, J=7.5, 1.0 Hz, 1H), 7.60-7.63 (m, 1H), 7.53 (d, J=8.0 Hz,1H), 7.38 (br. s., 1H), 7.34 (t, J=7.8 Hz, 1H), 4.26 (t, J=4.3 Hz, 4H),3.94 (t, J=4.5 Hz, 4H), 3.72 (s, 2H), 2.69-2.75 (m, 2H), 2.48-2.65 (m,10H).

MS (ES⁺) 523.2 (100%, [M+H]⁺).

Example SCyclopropyl-[2-(1H-indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl]-methyl-amine

i.2-(1H-Indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine-8-carbaldehyde,23

To compound 8 (as per Example H above) (40 mg, 0.13 mmol, 1 eq),indole-4-boronic acid (61 mg, 0.38 mmol, 3 eq) and PdCl₂(PPh₃)₂ (18.0mg, 0.03 mmol, 20 mol %) in a mixture of toluene (2.5 mL), ethanol (1.5mL) and H₂O (0.8 mL) was added NaHCO₃ (32 mg, 0.38 mmol, 3 eq) underAr(g). The reaction mixture was heated in a microwave for 1 h at 120° C.Once cooled down, the mixture was partitioned with H₂O (10 mL) andextracted with CH₂Cl₂ (2×10 mL) and EtOAc (2×10 mL). The combinedorganic extracts were dried over MgSO₄ and the solvent was removed invacuo. The resulting residue was further purified by silica gel columnchromatography with CH₂Cl₂/MeOH (1:0-19:1) to yield the product, 23, asa pale yellow solid (33.0 mg, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ_(H): 11.27 (br. s, 1H), 10.26 (s, 1H), 9.16(d, J=2.3 Hz, 1H), 9.11 (d, J=2.3 Hz, 1H), 8.18 (d, J=7.5 Hz, 1H),7.58-7.67 (m, 2H), 7.49 (t, J=2.8 Hz, 1H), 7.23 (t, J=7.7 Hz, 1H),4.08-4.16 (m, 4H), 3.83-3.90 (m, 4H).

MS (ES⁺) 432.0 (100%, [M+H+MeOH]⁺).

ii.Cyclopropyl-[2-(1H-indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl]-methyl-amine,S

To a solution of compound 23 (19 mg, 0.048 mmol, 1 eq), NaBH₃CN (6.0 mg,0.096 mmol. 2 eq), NaBH(OAc)₃ (31 mg, 0.144 mmol, 3 eq) in a mixture ofanhydrous CH₂Cl₂ (2 mL), MeOH (2 mL) and DMF (0.5 mL) was addedcyclopropyl-methyl-amine (19 μL, 0.19 mmol, 4 eq) under Ar(g). Thereaction mixture was stirred at rt overnight, and the solvents wereremoved in vacuo. The resulting residue was then partitioned with H₂O(10 mL) and extracted with CH₂Cl₂ (3×10 mL) and EtOAc (2×10 mL). Thecombined organic extracts were dried over MgSO₄ and the solvent wasremoved in vacuo. The residue was further purified by silica gel columnchromatography with CH₂Cl₂/MeOH (1:0-24:1) to furnish the product, S, asa white solid (9.56 mg, 44%).

¹H NMR (300 MHz, CDCl₃) δ_(H): 8.55 (d, J=2.3 Hz, 1H), 8.50 (d, J=2.3Hz, 1H), 8.33 (br. s., 1H), 8.23 (dd, J=7.5, 0.8 Hz, 1H), 7.58-7.63 (m,1H), 7.50-7.56 (m, 1H), 7.37-7.40 (m, 1H), 7.30-7.37 (m, 1H), 4.22-4.30(m, 4H), 3.91-3.98 (m, 4H), 3.89 (s, 2H), 2.33 (s, 2H), 1.76-1.84 (m,1H), 0.43-0.58 (m, 4H).

MS (ES⁺) 455.1 (100%, [M+H]⁺).

Example TCyclopropylmethyl-[2-(1H-indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-8-ylmethyl]-methyl-amine

To a solution of compound 23 (as per Example S above) (19 mg, 0.048mmol, 1 eq), NaBH₃CN (6.0 mg, 0.096 mmol. 2 eq), NaBH(OAc)₃ (31 mg,0.144 mmol, 3 eq), NaOAc (15.7 mg, 0.19 mmol, 4 eq) in a mixture ofanhydrous CH₂Cl₂ (2 mL), MeOH (2 mL) and DMF (0.5 mL) was addedcyclopropylmethyl-methyl-amine hydrochloride (23 mg, 0.19 mmol, 4 eq)under Ar(g). The reaction mixture was stirred at rt overnight. Solventswere removed in vacuo. Then, the residue was partitioned with H₂O (10mL) and extracted with CH₂Cl₂ (3×10 mL) and EtOAc (2×10 mL). Thecombined organic extracts were dried over MgSO₄ and the solvent wasremoved in vacuo. The residue was further purified by silica gel columnchromatography with CH₂Cl₂/MeOH (1:0-47:3) to yield the product, T, as awhite solid (8.35 mg, 37%).

¹H NMR (300 MHz, CDCl₃+10% CD₃OD) δ_(H): 8.57 (d, J=2.3 Hz, 1H), 8.49(d, J=2.3 Hz, 1H), 8.05 (dd, J=7.5, 1.1 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H),7.37 (dd, J=3.4, 0.8 Hz, 1H), 7.30 (d, J=3.4 Hz, 1H), 7.19-7.26 (m, 1H),4.16-4.22 (m, 4H), 3.84-3.90 (m, 4H), 3.75 (s, 2H), 2.32 (d, J=6.8 Hz,2H), 2.29 (s, 3H), 0.46-0.54 (m, 2H), 0.04-0.12 (m, 2H).

MS (ES⁺) 469.1 (100%, [M+H]⁺).

Example U8-Azetidin-1-ylmethyl-2-(1H-indol-4-yl)-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine

To compound 23 (as per Example S above) (17 mg, 0.04 mmol) in a mixtureof dry DMF (2 mL), CH₂Cl₂ (0.5 mL) and MeOH (0.2 mL) was added azetidinehydrochloride (16 mg, 0.17 mmol) and NaOAc (14 mg, 0.17 mmol) underAr(g). After 5 minutes NaBH(OAc)₃ (27 mg, 0.13 mmol) and NaBH₃CN (5.4mg, 0.09 mmol) were added and the reaction mixture was stirred for 16 h.EtOAc (45 mL) was added along with 50% saturated brine (5 mL): thelayers were separated, extracted with EtOAc (3×10 mL), dried (MgSO₄) andconcentrated in vacuo. Purification by flash column chromatography onsilica (eluant 2-8% MeOH/CH₂Cl₂) furnished U (5.4 mg, 0.012 mmol, 28%)as an off-white solid.

¹H NMR (300 MHz, 9:1 CDCl₃/CD₃OD) δ_(H): 8.52 (d, J=2.3 Hz, 1H), 8.43(d, J=2.3 Hz, 1H), 8.02 (dd, J=7.5, 1.1 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H),7.34 (dd, J=3.4, 0.8 Hz, 1H), 7.29 (d, J=3.0 Hz, 1H), 7.22 (t, J=7.8 Hz,1H), 4.15-4.21 (m, 4H), 3.83-3.89 (m, 4H), 3.73 (s, 2H), 3.20-3.33 (m,4H), 2.01-2.15 (m, 2H).

LCMS (ES⁺) 441 (100%, [M+H]⁺).

Biological Data 1) PI3K Isoform Biochemical Data

IC₅₀ (nM) PI3K Compound p110α p110β p110δ p110γ A 54 137 15 873 B 159 196 317 D 104 57 33 103 E 88 69 7 627 F 127 109 6 269 G 223 83 5 1655 H398 63 6 213 I 508 503 10 4946 J 680 277 26 1039 K 355 64 6 2612 L 604111 21 1820 M 96 25 10 219 R 597 131 22 2536

2) Anti-Inflammatory Activity: Inhibition of the Production ofPro-Inflammatory Cytokines from Stimulated Human Peripheral BloodMononuclear Cells (hPBMCs)

Compounds were tested at a concentration of 1 uM for cytokine releaseinhibition in hPBMCs stimulated with LPS (TNFα), PHA (IFNγ) and anti-CD3(IL-17A, IL-17F, IL-21, IL-23):

% Inhibition of Proinflammatory Cytokine Production at 1 uM CompoundTNFα IFNγ IL-17A IL-17F IL-21 IL-23 B 26 73 99 96 96 94 F 74 67 77 74 8293 H 75 87 99 96 96 93 I 61 80 95 95 96 90

3) In Vitro Inhibition of Rheumatoid Arthritis Synovial Fibroblast(RASF) Proliferation

Compound IC₅₀ (nM) RASF Proliferation A 1347 B 817 F 2237 H 1901 I 5722K 3020 M 1610

4) In Vitro Inhibition of Tumour Cell Proliferation

IC₅₀ (nM) PC3 (Prostate MCF7 (Breast A549 (Lung Compound Tumour) Tumour)Tumour) A 3013 331 151 B 1339 145 229 F 7294 215 1152 G 3770 127 186 H3030 165 466 K 3336 352 682 L 3244 119 1605

The invention claimed is:
 1. A compound represented by formula I:

or a pharmaceutically acceptable salt thereof, wherein: W is O; X is CH;R² is (LQ)_(m)Y; m is 1; L is C₁alkylene: Q is selected from the groupconsisting of: a direct bond, —NR³—, and a heterocyclic linker; Y isselected from the group consisting of: H, C₁₋₁₀alkyl, —OR³, and—C(O)N(R³)₂; and R³ is independently selected for each occurrence from Hor C₁-C₁₀ alkyl.
 2. The compound of claim 1, wherein both of the R₃groups that are attached to the 6,5-ring system in formula I are H. 3.The compound of claim 1, wherein Q is a heterocyclic linker and Y is H.4. A compound represented by:

or a pharmaceutically acceptable salt thereof, wherein: W is O; X is CH;R² is (LQ)_(m)Y; m is 1; L is C₁alkylene; Q is NR³; Y is heterocycle;and R³ is independently selected for each occurrence from H or C₁-C₁₀alkyl.
 5. A pharmaceutical composition comprising a compound of claim 1and a pharmaceutically acceptable excipient.